Review Article Vitamin A and Retinoids as Mitochondrial Toxicantsdownloads.hindawi.com/journals/omcl/2015/140267.pdf · 2015-11-23 · Vitamin A and Retinoids as Mitochondrial Toxicants

Review ArticleVitamin A and Retinoids as Mitochondrial Toxicants

Marcos Roberto de Oliveira

Department of Chemistry ICET Federal University of Mato Grosso (UFMT) Avenida Fernando Correa da CostaNo 2367 78060-900 Cuiaba MT Brazil

Correspondence should be addressed to Marcos Roberto de Oliveira mrobioqgmailcom

Received 10 December 2014 Accepted 30 April 2015

Academic Editor Angel Catala

Copyright copy 2015 Marcos Roberto de Oliveira This is an open access article distributed under the Creative Commons AttributionLicense which permits unrestricted use distribution and reproduction in any medium provided the original work is properlycited

Vitamin A and its derivatives the retinoids are micronutrient necessary for the human diet in order to maintain several cellularfunctions from human development to adulthood and also through aging Furthermore vitamin A and retinoids are utilizedpharmacologically in the treatment of some diseases as for instance dermatological disturbances and some types of cancer In spiteof being an essential micronutrient with clinical application vitamin A exerts several toxic effects regarding redox environment andmitochondrial function Moreover decreased life quality and increased mortality rates among vitamin A supplements users havebeen reported However the exact mechanism by which vitamin A elicits its deleterious effects is not clear yet In this review therole of mitochondrial dysfunction in the mechanism of vitamin A-induced toxicity is discussed

1 Introduction

Vitamin A (retinol) is a micronutrient present in bothvegetal and animal diets [1 2] However humans may beexposed to vitamin A and its derivatives (the retinoids)also pharmacologically as in the case of therapy for der-matological disturbances acute promyelocytic leukemia andimmunodeficiency treatment [3ndash9] to cite a few Duringleukemia treatment vitamin A at doses exceeding 150000ndash300000 IUday is administrated to children at different agesand young adults [8] Moreover vitamin A (as retinol palmi-tate) is administrated to very-low-weight-preterm infants(which may born weighting 08ndash11 kg) at doses exceeding8500 IUkgsdotdayminus1 during weight gain therapy for undeter-mined period [10] Recently it was reported that vitamin Asupplementation at 100000 to 200000 IU to children aged6 to 23 months did not prevent mortality in Guinea-Bissau[11] It is important to keep in mind that the RecommendedDietary Allowance (RDA) for vitamin A varies from 400mcgretinol activity equivalents (RAE to conversion please utilize1 IU retinol = 03mcg RAE) to 900mcg RAE in males from0 to 6 months to +51 years old and from 400mcg RAE to700mcg RAE in females from the same varying age [2 12]Then the levels of circulating vitaminAmay be exceeded dueto both inadvertent or clinical utilization

Really a panoply of side effects has been observedthat result from vitamin A intoxication that varies fromacute intoxication including for example headache hepaticswelling vomiting and diarrhea to chronic intoxication withinduction of cognitive decline in subjects at different agesas observed in the cases of increased irritability confusionanxiety disorders depression and suicide ideation [8 9 13]The exact mechanism by which vitamin A and retinoids exertsuch effects is not clear yet However it may include cellcycle disarrangement mitochondrial dysfunction oxidativeand nitrosative stress induction and activation of cell deathsignaling in different experimental models

In this work the effects of vitamin A and retinoids onsome redox and bioenergetics parameters will be discussedfocusing onmitochondrial function in different experimentalmodels

2 Vitamin A Metabolism A Brief Overview

Vitamin A (or retinol a diterpene) is originated fromisoprene units and is characterized as an isoprenoid witha hydrocarbon chain containing a hydroxyl group at oneend The oxidation of such hydroxyl group yields retinal (analdehyde retinaldehyde) or retinoic acid (a carboxylic acid)the biologically active forms of retinol In a general view

Hindawi Publishing CorporationOxidative Medicine and Cellular LongevityVolume 2015 Article ID 140267 13 pageshttpdxdoiorg1011552015140267

2 Oxidative Medicine and Cellular Longevity

all retinoids are formed by a 120573-ionone ring and a polyun-saturated side chain and a chemical group varying fromalcohol to carboxylic acid or ester as mentioned above Thepresence of conjugated double bonds is noteworthy whichmay be in either trans-configuration or cis-configuration inthe molecule of retinoids [14 15] Such chemical structuredecreases its solubility in aqueous environments

Vitamin A (retinol) and its derivatives the retinoidsparticipate in a myriad of biological processes during animallife from development to adulthood and aging Controlof cell proliferation differentiation induction of cell deaththrough apoptosis formation and shaping of the embryoorganogenesis and tissue homeostasis depend on physi-ological concentrations of vitamin A to occur adequately[9 14ndash16] Among retinoids all-trans retinoic acid is betterstudied because it is the most biologically potent vitamin Aderivative [9 12 14 15] Vitamin A and retinoids may exerttheir functions by binding to nuclear receptors (genomicaction induction or repression of the expression of targetgenes) or though regulation of signaling pathway dependenton phosphorylation of specific targets (nongenomic actiona rapid way to regulate cell events through the action ofprotein kinases and phosphatases) that culminate in a cellularresponse to such stimulus [12 14 15 17ndash19]

VitaminAmay be obtained from both vegetal and animaldiets 120573-Carotene (an isoprenoid compound) is convertedto two molecules of all-trans-retinal by centric oxidativecleavage and all-trans-retinal is reduced to all-trans-retinolwhichmay be esterified and stored in large amounts in tissuesas liver lung and fat [12 20 21] In the eyes retinoids areconverted to 11-cis-retinal which is a visual chromophore thatbinds to opsin in order to translate light into an electricalsignal [22 23] Esterified retinol in the form of retinolpalmitate is a major source of vitamin A from diet of animalorigin as for instance liver which stores the excess ofvitamin A [14 15 20 24]

The absorption of fat-soluble micronutrients occurs verysimilarly to that observed in lipids in the upper gastroin-testinal tract [25 26] after dissolution via formation oflipid droplets in both stomach and duodenum [27 28] Theesterified forms of vitamin A (mainly retinol palmitate) arefirstly hydrolyzed in the duodenum and the free form is thenabsorbed by the intestinal mucosa [29] It is suggested thattwo pancreatic enzymes perform such hydrolysis namelycholesterol ester hydrolase and pancreatic lipase [30ndash32]Then the enterocyte will absorb vitamin A and carotenoidswhich are incorporated into micelles with other lipids fromdiet [25 26] It was reported that the efficiency of retinolabsorption is around 75 [33] and 100 [34ndash37] On theother hand the efficiency of 120573-carotene absorption wasestimated to be from 3 to 90 [36ndash38] It was proposed thatenterocytes present a specific retinol transporter that func-tions very efficiently [39 40] The absorption of carotenoidsoccurs mainly through passive diffusion [41]

After enterocyte uptake retinol is esterified by lecithinretinol acyltransferase (LRAT which utilizes phosphatidyl-choline as acyl group donor) and acyl-CoA acyltransferase(ARAT) leading to the formation of retinol palmitateretinol oleate and retinol linoleate among others [25 42]

Carotenoids may follow one of these paths inside entero-cytes stay not metabolized (around 40 of provitamin Acarotenoids) be cleavage generating retinal via the reactionmediated by 120573-carotene-15151015840-monooxygenase or be cleav-age by mitochondrial 120573-carotene-91015840101015840-dioxygenase whichis responsible for the formation of apocarotenoids [43]

In the cytosol of the enterocyte retinol and its derivatives(mainly retinal and retinoic acids) bind to specific proteinscalled cellular retinol-binding protein II (CRBP II) [25]In other cells as for instance the hepatocytes CRBP Iis responsible for free retinol transport Additionally thebinding of retinol to CRBP is necessary to its esterificationby LRAT or ARAT In the hepatocytes esterified retinol andretinal are also transported by CRBP I In the plasma retinolis transported by retinol binding protein (RBP) to generaldistribution to tissues [14 15] Retinol is converted to retinalby either microsomal or cytosolic retinol dehydrogenase(RoDH) isozymes In turn retinal is converted in retinoicacid by cytosolic retinal dehydrogenase (RalDH) [14 15 44]Retinoic acids bind to cellular retinoic acid binding protein(CRABP) in cytosol and it is suggested that this complexmigrates to nucleus to exert its effects through binding tonuclear receptors to retinoic acid (RAR or RXR) [44 45]

Central nervous system (CNS) cells also possess nuclearreceptors CRBPs and CRABPs as well as enzymes necessaryto the local metabolism of vitamin A and derivatives Addi-tionally it has been postulated that retinoids may act througha nongenomic way in different cell types including neurons[46 47]The role of retinoids is not restricted to developmentof CNS It has been shown that retinoids are responsible forsynaptic plasticity of the hippocampus for maintenance ofdopamine signaling inmesolimbic andmesostriatal neuronsand for survival of nigrostriatal dopaminergic neurons [48ndash50]

3 The Relationship of Vitamin A andRetinoids with Biological Membranes

The hydrophobicity of vitamin A and retinoids is a chemicallimiting its distribution in the aqueous compartments ofthe body As mentioned above it is necessary to bind suchmolecules to transport protein to increase its solubilityIndeed vitamin A reacts with hydrophobic environments asfor example biologicalmembranes andmay interferewith itsphysiology by perturbing phospholipid and steroids home-ostasis It was previously demonstrated that retinol inducedhemolysis by penetrating rabbit erythrocytes and disruptingphysical structure of the membranes [51] According to theauthors such effect did not depend on oxidation of retinoland formation of free radicals However it was observedthat cotreatment with vitamin E alleviated hemolysis In thatwork it was suggested that vitamin E did act by decreasingpermeability and fluidity and not through its antioxidantcapacity In other works the authors found that the retinol-induced hemolysis was dependent on hydroxyl radical for-mation [52] Goodall et al demonstrated that retinol andretinoids (retinaldehyde 120572-retinoic acid iso-13-retinol andretinyl acetate) induced cell fusion hemolysis and swelling

Oxidative Medicine and Cellular Longevity 3

of mitochondria [53] Actually intravascular administrationof all-trans retinoic acid to patients under treatment of acutepromyelocytic leukaemia induced hemolysis and compli-cated the continuation of this clinical procedure [54]

Overall such findings indicate a potential ability ofvitamin A and its derivatives to negatively interact withbiological membranes an event that may lead to organellestress as for instance mitochondrial dysfunction and to cellapoptosis or necrosis

4 The Effects of Vitamin A and ItsDerivatives on Mitochondrial Membranesand Organelle Physiology

41 In Vitro Effects of Vitamin A on Mitochondria As pre-viously mentioned retinol induced mitochondrial swellingand disrupted membrane organization in in vitro assays[51ndash54] Rigobello et al [55] did demonstrate that differentretinoic acids (namely all-trans 9-cis and 13-cis retinoicacids) were able to induce swelling of the organelle isolatedfrom rat liver All the retinoids tested induced membranepermeability transition (which was observed as swelling) anddecreased membrane potential Interestingly neither EGTA(Ca2+ ion chelating agent) nor cyclosporin A (CsA) inhibitedthe effects elicited by 13-cis retinoic acid Additionally 13-cis retinoic acid induced cytochrome c release from theorganelle an event that is necessary to trigger the intrinsicapoptotic pathway [56] Later it was reported that retinolalso altered mitochondrial structure by inducing swellingand lipid peroxidation in mitochondrial membranes in vitro[57] In addition retinol induced cytochrome c release andincreased superoxide anion radical (O2

minus∙) production ina dose-dependent pattern When analyzed together suchresults indicate part of the mechanism by which retinoland retinoids may trigger cell death through the mitochon-drialintrinsic pathway Also it demonstrates that vitaminA may exert prooxidant effects by altering mitochondrialfunction and favoring electron leakage from mitochondrialeading to increased free radical generation

Really it was demonstrated that retinol induced apop-tosis in cultured Sertoli cells by a mitochondria-dependentpathway [58] In such work the researchers found thatretinol induced a decrease in cell viability and ATP con-tent and increased O2

minus∙ formation Additionally increasedcytochrome c release to the cytosol and consequentlyincreased caspase-37 enzyme activity were observed Thenfrom isolated mitochondria assays to cultured cells thedeleterious effects of vitamin A on mitochondria may beobserved Such negative action of this vitamin and its deriva-tives on mitochondrial function andor dynamics may resultin cell deathThe release of cytochrome c to cytosol may leadto two important processes increased O2

minus∙ production andapoptosis through formation of the apoptosome Howeverapoptosis is dependent on sufficient ATP levels because theapoptosome consumes ATP (or dATP) to cleave and activatecaspases Then deregulated cytochrome c release may leadthe cells to die by necrosis which induces inflammation

an evenmore deleterious process to cell viability (for a reviewplease see [56])

Silva et al reported that acitretin (a synthetic retinoid thatis used in the treatment of severe extensive psoriasis) at 5ndash20120583M altered the function of rat liver mitochondria in vitro[59] The authors found impaired phosphorylation capacitydecreased ATP levels and adenine nucleotide translocase(ANT) content and Ca2+-induced mPTP (mitochondrialpermeability transition pore) On the other hand decreasedmembrane potential was not observed Surprisingly sucheffects were not reverted by the cotreatment with thiol groupreductants or other antioxidant agents showing at least inpart that a redox mechanism did not take part in the eventsobserved On the other hand mPTP was blocked by ANTligands as for instance ATP and ADP

Recently Sawada et al reported that all-trans-retinal (10ndash30 120583M) a byproduct of the visual cycle (originated fromthe chromophore 11-cis-retinal) decreased viability of ARPE-19 cell line and induced oxidative stress-dependent Baxactivation through PLCIP3Ca2+ signals and by activationof p53 following DNA damage [60] The authors concludethat all-trans-retinal affected cell viability by a mechanismthat increased the concentration of cytosolic Ca2+ ions whichlead to oxidative stress and DNA damage In turn it activatesp53 through a mechanism dependent on phosphorylationof ser46 residue and translocation to the cytosol where itactivates Bax triggering apoptosis This work demonstratesthe importance of maintaining the levels of all-trans-retinalunder control in retina since disrupted all-trans-retinalclearance may lead to retinopathy as previously reported[61] However the authors did not investigate the role ofmitochondria in the induction of apoptosis in that work

A synthetic retinoid (ST1926) was recently tested fortreating adult T-cell leukemialymphoma and demonstratedability to induce growth arrest and apoptosis of T malignantcells [62] ST1926 at 1 120583M for 48 hours induced apoptosis inHuT-102MT-2 Jurkat andMolt-4 cell lines Even though theapoptotic mechanism depends on caspase-3 any parameterrelated to mitochondrial dynamics was not investigated inthat work

42 In Vivo Effects of Vitamin A onMitochondria The effectsof vitamin A and retinoids on mitochondrial function werewell investigated in vitro However recently it was demon-strated that intragastric (gavage) vitamin A supplementationat pharmacological doses (from 1000 to 9000 IUkgsdotdayminus1)for 3 7 or 28 days induced redox (Table 1) and bioenergetics(Table 2) impairments in rat brain regions and other tissuesof adult male Wistar rats as discussed below Additionallysome abnormalities in behavioral tasks were observed as forexample in the open field and light-dark box [63ndash66]

Vitamin A supplementation increased mitochondrialsuperoxide anion radical (O2

minus∙) production (Table 3) andinduced lipid peroxidation protein carbonylation and nitra-tion and oxidation of protein thiol groups in mitochondrialmembranes isolated from rat cerebral cortex cerebellumsubstantia nigra striatum frontal cortex and hypothalamus[67ndash69 76 78] In the same rat brain areas increased


Table 1 Summary of the in vivo effects of subacute vitamin A supplementation on mitochondrial membranes parameters

Sample Lipid peroxidation Protein carbonylation Protein nitration Protein thiol content ReferenceCerebral cortex uarr uarr Not measured darr [65]Cerebellum uarr uarr Not measured darr [65]Substantia nigra uarr Not measured Not measured Not measured [67]Striatum uarr Not measured Not measured Not measured [67]Hypothalamus uarr Not measured Not measured Not measured [68]Frontal cortex uarr uarr uarr Unaltered [69 70]Hippocampus uarr uarr uarr Unaltered [70 71]Liver uarr uarr Not measured Unaltered [72 73]Heart Not measured Not measured uarr Not measured [74]Lung uarr uarr uarr Unaltered [75]Adult male rats were treated with vitamin A supplementation (1000ndash9000 IUkgday) subacutely (see text for details)

Table 2 Summary of in vivo effects of subacute vitamin A supplementation on mitochondrial function parameters

Sample Complexes IndashIII Complexes II-III Complexes II + SDH Complex IV ReferenceCerebral cortex Not measured Not measured Not measured Not measured mdashCerebellum uarr Unaltered Unaltered darr [76]Substantia nigra uarr uarr uarr Unaltered [67]Striatum uarr Unaltered Unaltered darr [67]Hypothalamus uarr Unaltered Unaltered darr [68]Frontal cortex uarr Unaltered Unaltered Unaltered [69 70]Hippocampus uarr Unaltered Unaltered darr [70 71]Liver uarr uarr uarr uarr [72 73]Heart darr darr darr Not measured [74]Lung uarr uarr uarr Not measured [75]Adult male rats were treated with vitamin A supplementation (1000ndash9000 IUkgday) subacutely (see text for details)

complex IndashIII enzyme activity was observed [67ndash69 76 78]However a proportional increase in the following complexesof themitochondrial electron transfer chain (METC) was notfound as expected For example vitamin A supplementationinduced a decrease in complex IV enzyme activity in ratcerebellum striatum and hypothalamus [67 68 76] Onthe other hand any change in some complexes activitieswas not observed as follows complexes II II-III and suc-cinate dehydrogenase (SDH) (cerebellum) [76] complex IV(substantia nigra) [67] complexes II-III and SDH (striatumhypothalamus) ([67] [68] resp) complexes II-III SDH andcomplex IV (frontal cortex) [69] (Table 2) Such impairmentin electron flux between mitochondrial complexes may favorelectron leakage from the electron transfer chain since theelectron flux is higher between some complexes but thereduction of O

2

to water is not occurring at the same rate dueto unaltered or even decreased complex IV enzyme activity(Figure 1) Also more O

2

is available to react with electrondonors and becomes O2

minus∙ [79 80] Furthermore increasedcomplexes IndashIII II-III and II and SDH and complex IVenzyme activitieswere also reported in the liver of the animalsthat receive vitamin A supplementation at clinical doses for28 days [72] These findings are different from that observedin brain regions of the animals that received vitamin A for thesame period as described above since it was demonstratedthat complex IV enzyme activity was increased at a very

similar rate when compared to complexes IndashIII in rat liverHowever such increment in the electron flux between theelectron transfer chain (ETC) complexes was accompaniedby a proportional increase in O2

minus∙ production (Table 3) Thisresult may suggest that O2

minus∙ is being produced by mitochon-dria isolated from vitamin A-treated rats by a mechanismthat is not obligatorily associated with uncoupling of the ETCactivity

More recently it was published that vitamin A sup-plementation induced an increase in total 3-nitrotyrosinecontent in rat cerebral cortex hippocampus substantia nigrastriatum hypothalamus heart and lung [67 68 71 7475 81] In addition increased 3-nitrotyrosine content inproteins located in the mitochondrial membranes isolatedfrom frontal cortex hippocampus heart and lung of vitaminA-treated rats was reported [69 71 74 75] (Table 1) The for-mation of 3-nitrotyrosine is a consequence of increased levelsof O2minus∙ and NO∙ which give rise to peroxynitrite (ONOOminus)

that may react with tyrosine residues in proteins leading tothe formation of 3-nitrotyrosine Additionally ONOOminus maygive rise to peroxynitrous acid (ONOOH) which producesnitryl cation (NO2+) nitrogen dioxide radical (∙NO2) andhydroxyl radical (∙OH) through homolytic fission reaction[82 83] At least in part the increase in 3-nitrotyrosinecontent may be explained by the increase in mitochondrialO2minus∙ production elicited directly or indirectly by vitamin


Table 3 Summary of in vivo effects of subacute vitamin A supplementation on mitochondrial redox parameters

Sample Superoxide anion radical Mn-SOD enzyme activity MAO enzyme activity ReferenceCerebral cortex uarr Not measured Not measured [65]Cerebellum uarr Not measured Not measured [65]Substantia nigra uarr uarr Unaltered [67]Striatum uarr uarr uarr [67]Hypothalamus uarr Not measured Not measured [68]Frontal cortex uarr uarr uarr [77]Hippocampus uarr uarr uarr [77]Liver uarr Not measured Not measured [73]Heart Not measured Not measured Not measured mdashLung uarr Not measured Not measured [75]Adult male rats were treated with vitamin A supplementation subacutely (see text for details)

Vitamin A

activity

IV enzyme activity METC

production

Mn-SODenzyme activity

uarr Electron leakage from

+

H2O2

O2minus∙

uarr Mitochondrial O2minus∙

uarr MAO

(ii) Unaltered or darr complex

(i) uarr Complexes IndashIII enzyme

Figure 1 A schematic diagram summarizing the effects of in vivovitamin A supplementation on mitochondrial function regardingthe mitochondrial electron transfer chain (METC) enzyme activityMitochondrial dysfunction may lead to increased O2

minus∙ productionthrough electron leakage and partial reduction of O

2

Mn-SODconvertsO2

minus∙ toH2

O2

and togetherwithMAO favors an increase inthe levels of H

2

O2

in different cell types (please see text for details)H2

O2

is able to react with iron ions generating ∙OH (the mostpowerful ROS) through Fenton chemistry reaction (not shown) forexample leading to widespread redox disturbances

A supplementation In order to investigate whether NO∙production (as indirectly assessed through 3-nitrotyrosineformation) participates in mitochondrial dysfunction andbehavioral disturbances observed in the experimental modelof vitamin A supplementation the role of a cotreatmentwith L-NG-nitroarginine methyl ester was tested (L-NAME30mgkg four times a week) a nonspecific nitric oxidesynthase (NOS) inhibitor on such parameters InterestinglyL-NAME cotreatment did not exert any effect on the redox

unbalance elicited by vitamin A on rat frontal cortex hip-pocampus substantia nigra and striatum [77]

It was previously described that increased formation ratesof 3-nitrotyrosine favor protein aggregation which may leadto serious consequences regarding mitochondrial functionsuch as import of molecules (from metabolic substratesto proteins necessary to the ETC function among others)from cytosol and other complex processes as mitochondrialfusion and fission Both 120572-synuclein and 120572-tubulin may benitrated and form protein aggregates that accumulate incytoplasm [84ndash86] 120572-Synuclein has been implicated in themechanism behind the pathogenesis of neurodegenerativesynucleinopathies [84 87] Recently it was shown that 120572-synuclein may interact negatively with mitochondria causingit to lose transmembrane potential and decrease phospho-rylation capacity [88] In fact 120572-synuclein may bind to theinner mitochondrial membrane in 120572-helical conformation[89] Interestingly increased levels of 120572-synuclein but unal-tered levels of 120573-synuclein in brain regions of vitamin A-treated rats were demonstrated [67 71 77] However neitheralterations in 120572-synuclein structure nor interactions of suchprotein with mitochondria in the experimental model ofvitamin A supplementation were investigated

On the other hand it was shown that vitamin A supple-mentation for 28 days increased monoamine oxidase (MAO)enzyme activity in both areas of the nigrostriatal axis andhippocampus [71 77 90] (Table 3) MAO is responsible forthe chemical inactivation of dopamine and serotonin andproduces H

2

O2

in such reaction [87 91] MAO is locatedin the outer mitochondrial membrane facing the cytosolbut H

2

O2

is a membrane soluble ROS and may enter mito-chondria or other organelles [91] Taken together such dataindicate mitochondria as an important source of H

2

O2

sincemanganese-superoxide dismutase (Mn-SODmitochondrial)and MAO enzyme activities were found increased in thehippocampus and nigrostriatal axis of vitamin A-treated rats[71 90] (Table 3) H

2

O2

which is also water soluble maydiffuse to places far away from its origin disseminating theredox impairment from one cellular environment to another[92ndash97] (Figure 1) Interestingly CAT enzyme activity wasfound either unaltered or decreased in brain areas of vitaminA-exposed rats [63 64 66] Such finding suggests that


minus

H2O2 + O2 2H2O + O2uarr 2O2minus∙

uarr SOD darr CAT

Figure 2 Unbalanced SODCAT ratio resulting in increased H2

O2

production Additionally increased O2minus∙ levels inhibit CAT enzyme

activity allosterically leading to evenmore highH2

O2

concentrationdue to accumulation of this ROS

an impairment exists also on the ratio between SOD andCAT enzyme activities which may favor an increase inH2

O2

production Furthermore accumulated O2minus∙ is able to

inhibit CAT enzyme activity as well as other enzymes [98](Figure 2)Then itmay be suggested that in the experimentalmodel of vitamin A supplementation mitochondria is abiological source of H

2

O2

in some rat brain regions and sucheffect may be linked to the oxidative stress observed in somereports (Figure 3)

In addition to a possible H2

O2

generation increaseincreased glutathione S-transferase (GST an enzyme that isresponsible for phase II detoxification reactions of conju-gation in several cell types) enzyme activity in the vitaminA supplementation experimental model was detected [6776] Such enzyme consumes reduced glutathione (GSH) toproduce more polar xenobiotics that are easily excreted fromcells [99] By consuming GSH at increased rates it mayfacilitate the perpetuation of H

2

O2

prooxidant signal sinceGSH is utilized by GPx in the conversion of H

2

O2

to water[87 100 101] In the nigrostriatal axis there is a high Fe2+content that may react with H

2

O2

through Fenton chemistryreaction in cases of hypervitaminosis A for example leadingto increased production of ∙OH the most powerful freeradical in biological systems [87 102 103] Indeed it mayfacilitate dopaminergic neuronal death by either apoptosis ornecrosis leading detrimental effects on movement controlas observed in patients suffering from Parkinsonrsquos disease[104 105] Although redox impairment was found in suchrat brain areas any alteration regarding cellular markers ofcell death was not observed such as caspase-3 or caspase-8enzyme activity [67ndash69 78 90]

43 Ex Vivo Effects of Vitamin A on Mitochondria VitaminA supplementation at clinical doses for 3 or 7 days inducedseveral prooxidant effects also on rat liver which is themain site of vitamin A storage in mammals [14 15 47]It was observed that vitamin A supplementation (1000 to9000 IUkgsdotdayminus1) for 3 or 7 days induced oxidative stressin mitochondrial membranes and increased O2

minus∙ production[73] Also increased complexes IndashIII enzyme activity wasdemonstrated without any effect on complexes II-III and IVHowever the more surprising in that work is the fact thatintact mitochondria isolated from the liver of the animalsthat received vitamin A supplementation were found to bemore sensitive to an incubation of 10 minutes with CaCl

2

at low concentration (75120583M ex vivo assay) Calcium ionsmediate mitochondrial dysfunction by increasing reactiveoxygen species (ROS) production and triggering mPTPresulting in apoptosis as reviewed elsewhere [106ndash108] A25- to 29-fold increase in lipid peroxidation levels in themitochondria isolated from vitamin A-treated rats whenexposed to CaCl

2

was detected Similar effects were seenwhen protein carbonylation and thiol oxidationmarkers werequantified in such experimental model Cotreatment withDTT GSH superoxide dismutase (SOD) or catalase (CAT)did decrease the prooxidant effect induced by CaCl

2

NeitherCsA nor bongkrekic acid (BKA) (mPTP inhibitors) did alterthe effect induced by CaCl

2

[73] Then such data suggestthat the prooxidant effects that appeared after exposure toCaCl2

are not related to mPTP formation AdditionallyCaCl2

amplified O2minus∙ production in intact mitochondria

isolated from vitamin A-treated animals However onlycotreatment with GSH or SOD did decrease CaCl

2

-inducedO2minus∙ production [73] Then it may be concluded that in

vivo vitamin A supplementation increased the ex vivo mito-chondrial susceptibility to a challenge that indirectly inducesa prooxidant state in the organelle However it was notassociated with mPTP formation as indicated through theutilization of mPTP inhibitors At least in part some of thefindings presented above are similar to the effects elicitedby the treatment with a synthetic retinoid (acitretin) onmitochondrial function in vitro [59]

The effects of vitamin A supplementation on a mitochon-drial challenging with CaCl

2

in the case of rat liver analyseswere discussed above However it was also investigatedwhether in vivo vitamin A supplementation altered brainmitochondria response to an ex vivo challenge with H

2

O2

or120573-amyloid peptide

1ndash40 and peptide1ndash42 [70 90] As expected

vitamin A supplementation increased the susceptibility ofmitochondria (isolated from the nigrostriatal axis and fromfrontal cortex and hippocampus) to H

2

O2

(a ROS) andto 120573-amyloid peptide

1ndash40 and peptide1ndash42 (which accumu-

late at both extra- and intraneuronal environments in thecase of Alzheimerrsquos disease) [87] 120573-Amyloid peptide

1ndash40and peptide

1ndash42 which may accumulate in the extracellularenvironment also are able to enter neurons and interactwith organelles such as mitochondria leading to membranerupture among other effects and general dysfunction [109ndash113] It is an important finding demonstrating that even rec-ommended doses of vitamin A (which have been consideredto be secure to humans) facilitate mitochondrial damagewhen such organelles are exposed to reactivemolecules (withor without radical nature) (Figure 4)

44 Other Evidences of Vitamin A-Induced Toxicity on Mam-malian Mitochondria It was also observed that vitaminA supplementation (1000ndash9000 IUkgsdotdayminus1 for 28 days)induced a decrease in the levels of brain-derived neurotrophicfactor (BDNF) in rat hippocampus [71] BDNF is a majorneurotrophin in the mammalian brain and is involved inthe induction of neuronal proliferation and maintenance ofneuron survival [114ndash116] Furthermore BDNF may signalmitochondrial biogenesis in different cell types including


Vitamin A

ER stress

Mitochondrial dysfunction

leakage

production

In mitochondrial membranes

A vicious cycle

activity

Substrate oxidation

enzyme activity

DiffusibleDisseminates oxidative

stress H2O2


darr BDNF

uarr Electron

uarr MAO enzyme

uarr Lipid peroxidation

uarr Protein carbonylation

uarr Protein nitration

uarr Oxidation of thiol protein groups

uarr Mn-SOD

uarr 120572-Synuclein

Figure 3 A general view of the effects of in vivo vitamin A supplementation in an animal experimental model It has been hypothesized thatvitamin A may induce mitochondrial dysfunction by different ways as follows (1) by decreasing BDNF levels (2) by inducing ER stress andcalcium ion metabolism deregulation andor (3) by increasing 120572-synuclein levels The increased O2

minus∙ levels may induce redox unbalance inthe organelle that in turn may generate more O2

minus∙ in a vicious cycle Increased H2

O2

production (by Mn-SOD and MAO enzymes) maydisseminate redox impairment from one region to another

neurons [117 118] Then BDNF is also responsible at least inpart for maintaining ATP homeostasis in mammalian cellsHowever a causal link between mitochondrial dysfunctionand deregulated BDNF levels was not established yet

Some evidences point to vitamin A as an inducer ofendoplasmic reticulum (ER) stress since increasedBiPGrp78levels in the hippocampus of vitamin A-treated rats wasreported [71] BiP (a protein chaperone) is a major regulatorof ER function and participates for example in proteinfolding and assembly binding to Ca2+ ions and controllingER stress sensors activation [130 131] Whether vitamin A orone of its derivatives alter ER function was not demonstratedyet but by inducing ER stress vitamin A may deregulateCa2+ ions homeostasis which may lead to mitochondrialdysfunction and cell death [132] (Figure 3)

5 Clinical Hypothesis of the Impact ofHypervitaminosis A on Human Health

Mitochondrial dysfunction gives rise to a myriad of conse-quences It includes bioenergetics deficits increased produc-tion of reactive oxygen or nitrogen species (ROS and RNSresp) and apoptosis or necrosisThen it is very important to

maintain mitochondrial homeostasis to avoid loss of cellularquality and death by mechanisms that may culminate ininflammation for example

It has been shown that retinoids possess an ability toalter cell cycle and to induce apoptosis in some experimentalmodels It was published that the treatment of adult micewith 13-cis-retinoic acid at 1mgkgsdotdayminus1 (a clinical dosecommonly applied in the treatment of nodular acne) for 1ndash6 weeks suppressed hippocampal cell division (neurogenesis)and consequently decreased capacity to learn in behavioraltask [133] Accordingly Sakai et al demonstrated increasedcell loss in the hippocampus of mice treated for 3 weeks with13-cis-retinoic acid at 1mgkgsdotdayminus1 [134]Themechanism bywhich 13-cis-retinoic acid altered neurogenesis and inducedcell death in mice hippocampus is not clear but it has beenreported that this retinoid may trigger apoptosis throughactivation of caspase-3 and by modulating bcl2 and p53gene expression in melanoma cells [135] Reinforcing thefinding that a retinoid may induce negative consequencesto hippocampal function it was reported that vitamin Asupplementation with retinol palmitate induced anxiety-likebehavior in adult rats [63] Anxiety is a behavior closelyrelated to alterations in the function of hippocampus and


Table 4 Clinical utilization of vitamin A and retinoids

Retinoid Utilization ReferenceVarious Prevention of infectious diseases [4]Retinol palmitate Treatment of acute promyelocytic leukemia [5 7]Retinol palmitate Treatment of acute nonlymphocytic leukemia [6]Various Weight gain therapy in preterm infants [10]Retinol palmitateacetate Immunotherapy (with vaccination) [11]Isotretinoin Acne therapy [119ndash124]Various Antioxidant therapy increased longevity (supplements) [125ndash127]Retinyl esters Treatment of infants born from HIV-positive women (immunodeficiency therapy) [128]Various Antioxidant therapy in heart disease [16]Various Utilization in general dermatology [129]

Vitamin A

In vivo effects onmitochondrial

membranes

susceptbility to ex vivochallenges with different chemical agents (amyloid

Is it an alternative road to cell death

(i) Neurodegeneration(ii) Other organs failure

uarr Mitochondrial

120573 peptides H2O2CaCl2)

(i) uarr O2minus∙ production

(ii) uarr Lipid peroxidation

(iii) uarr Protein carbonylation

(iv) uarr Protein nitration

(v) uarr Protien thiol oxidation

(vi) METC impairment

Figure 4 A general view of the consequences of in vivo vitaminA supplementation on the susceptibility of mitochondria to ex vivochallenges with different chemical agents Mitochondria isolatedfrom vitamin A-treated rats are more sensitive to different chemicalinsults including amyloid 120573 H

2

O2

and CaCl2

as discussed in thetext

significantly decreases human life quality [136ndash138] Further-more studies in humans demonstrated that the use of 13-cis-retinoic acid (as treatment to nodular acne) decreasedmetabolism in orbitofrontal cortex a region associated withdepression [119] Indeed there is a strong body of evi-dence showing that 13-cis-retinoic acid (isotretinoin) induceddepression and increased both suicide ideation and suiciderates among some patients under such treatment [120ndash124]However it remains to be elucidated whether there is acausal link between bioenergetics impairment and neuronaldysfunction that leads to detrimental alteration in humanbehavior

In fact the capacity of retinoids to induce mitochondrialdysfunction and cell death has been utilized pharmacologi-cally as a strategy to treat several human diseases from der-matological disturbances to some types of cancer (Table 4)On the other hand it is not clear whether a vitamin A

overload would be beneficial to cells under constant stressand low antioxidant defenses as for instance neurons [87139 140] Increased cell death rates are observed in thecase of Parkinsonrsquos disease and Alzheimerrsquos disease [87]and increased ingestion or other forms of exposure to suchvitamin may favor a more drastic situation with acceleratedneuronal loss and increased neuroinflammation Really it hasbeen reported that vitamin supplements utilization (includ-ing vitamin A and carotenoids) by well-nourished subjectsmay increase risk ofmortality among them [125ndash127] Indeedthe ingestion of antioxidant supplements in the primaryprevention of chronic diseases ormortality in agreementwithrecent dietary guidelines is not suggested [127] Additionallyit is alarming that the combination of 120573-carotene (30mgvitamin A precursor from vegetal diet) and retinol palmitate(25000 IU) supplementation increased lung cancer incidenceamong men and women in a clinical trial that has to bestopped due to increased lung cancer and death among thevolunteers [141] However the mechanisms by which vitaminA and retinoids among other lipophilic vitamins alter cellfunction leading to death remain to be elucidated

6 Conclusion

Vitamin A and its derivatives the retinoids disrupt mito-chondrial function by a mechanism that is not completelyunderstood However it accounts with impaired electron fluxbetween the complexes of theMETC increased ROS produc-tion and induction of oxidative and nitrosative stress tomito-chondrial membranes Additionally vitamin A and retinoidsalter the mitochondrial structure by causing swelling of theorganelle More investigations are needed to elucidate howvitamin A and retinoids affect mitochondria and whetherthere is a causative link between such event and the clinicalmanifestations observed both experimentally and in humans

Then even though more investigations in this field arenecessary it is more secure to take some caution when vita-min A has been ingested at higher than recommended levelsby individuals with familial history of neurodegenerativediseases for instance Alzheimerrsquos disease and Parkinsonrsquosdisease or are already affected by such irreversible disordersReally the fact that vitamin A increased susceptibility ofmitochondria to some common cellular stress inducer agents


(CaCl2

and H2

O2

and not only 120573-amyloid peptide1ndash40 and

peptide1ndash42) must be considered in the case of utilization of

such micronutrient as supplement or fortified food in anycase of disease not only those from neuronal origin

Overall caution must be taken when utilizing vitaminA or its derivatives in some specific conditions since suchmolecules regulate cell cycle and cell fate (survival or death)by different ways and its toxic effects may also lead toirreversible damage

Abbreviations

ANT Adenine nucleotide translocaseARAT Acyl-CoA acyltransferaseBDNF Brain-derived neurotrophic factorBKA Bongkrekic acidCNS Central nervous systemCRABP Cellular retinoic acid binding proteinCRBP I Cellular retinol-binding protein ICRBP II Cellular retinol-binding protein IICAT CatalaseCsA Cyclosporin AER Endoplasmic reticulumETC Electron transfer chainGSH GlutathioneGST Glutathione S-transferaseL-NAME L-NG-nitroarginine methyl esterLRAT Lecithin retinol acyltransferaseMAO Monoamine oxidaseMETC Mitochondrial electron transfer chainMn-SOD Manganese-superoxide dismutasemPTP Mitochondrial permeability transition poreNOS Nitric oxide synthaseRAE Retinol activity equivalentsRalDH Retinal dehydrogenaseRAR Retinoic acid receptorRBP Retinol binding proteinRDA Recommended Dietary AllowanceRNS Reactive nitrogen speciesRoDH Retinol dehydrogenaseROS Reactive oxygen speciesSDH Succinate dehydrogenaseSOD Superoxide dismutase

Conflict of Interests

The author declares that there is no conflict of interestsregarding the publication of this paper

Acknowledgments

Thanks are due to Fernanda Rafaela Jardim MS for Englishgrammar revision Some of the data discussed here wereobtained from research that was funded by CNPq

References

[1] D A Ross ldquoRecommendations for vitamin A supplementa-tionrdquo Journal of Nutrition vol 131 pp 2902Sndash2906S 2002

[2] S A Tanumihardjo ldquoAssessing vitamin A status past presentand futurerdquo The Journal of Nutrition vol 134 no 1 pp 290Sndash293S 2004

[3] L H Allen and M Haskell ldquoEstimating the potential forvitamin A toxicity in women and young childrenrdquo Journal ofNutrition vol 132 no 9 pp 2907Sndash2919S 2002

[4] P P Glasziou and D E M Mackerras ldquoVitamin A supplemen-tation in infectious diseases a meta-analysisrdquo British MedicalJournal vol 306 no 6874 pp 366ndash370 1993

[5] H Tsutani H Iwasaki Y Kawai et al ldquoReduction of leukemiacell growth in a patient with acute promyelocytic leukemiatreated by retinol palmitaterdquo Leukemia Research vol 14 no 7pp 595ndash600 1990

[6] H Tsutani T Ueda M Uchida and T Nakamura ldquoPhar-macological studies of retinol palmitate and its clinical effectin patients with acute non-lymphocytic leukemiardquo LeukemiaResearch vol 15 no 6 pp 463ndash471 1991

[7] P Fenaux C Chomienne and L Degos ldquoTreatment of acutepromyelocytic leukaemiardquo Best Practice and Research ClinicalHaematology vol 14 no 1 pp 153ndash174 2001

[8] A M Myhre M H Carlsen S K Boslashhn H L Wold PLaake and R Blomhoff ldquoWater-miscible emulsified and solidforms of retinol supplements are more toxic than oil-basedpreparationsrdquoAmerican Journal of ClinicalNutrition vol 78 no6 pp 1152ndash1159 2003

[9] KOrsquoReilly S J Bailey andMA Lane ldquoRetinoid-mediated reg-ulation of mood possible cellular mechanismsrdquo ExperimentalBiology and Medicine vol 233 no 3 pp 251ndash258 2008

[10] H Mactier and L T Weaver ldquoVitamin A and preterm infantswhat we know what we donrsquot know and what we need to knowrdquoArchives of Disease inChildhood Fetal andNeonatal Edition vol90 no 2 pp F103ndashF108 2005

[11] A B Fisker C Bale A Rodrigues et al ldquoHigh-dose vitaminA with vaccination after 6 months of age a randomized trialrdquoPediatrics vol 134 no 3 pp e739ndashe748 2014

[12] C A van Loo-Bouwman T H J Naber and G SchaafsmaldquoA review of vitamin A equivalency of 120573-carotene in variousfood matrices for human consumptionrdquo The British Journal ofNutrition vol 111 no 12 pp 2153ndash2166 2014

[13] S R Snodgrass ldquoVitamin neurotoxicityrdquo Molecular Neurobiol-ogy vol 6 no 1 pp 41ndash73 1992

[14] J L Napoli ldquoRetinoic acid its biosynthesis and metabolismrdquoProgress in Nucleic Acid Research andMolecular Biology vol 63pp 139ndash188 1999

[15] J L Napoli ldquoPhysiological insights into all-trans-retinoic acidbiosynthesisrdquo Biochimica et Biophysica ActamdashMolecular andCell Biology of Lipids vol 1821 no 1 pp 152ndash167 2012

[16] V P Palace N Khaper Q Qin and P K Singal ldquoAntioxidantpotentials of vitamin A and carotenoids and their relevance toheart diseaserdquo Free Radical Biology and Medicine vol 26 no5-6 pp 746ndash761 1999

[17] Y Li NWongsiriroj andW S Blaner ldquoThemultifaceted natureof retinoid transport and metabolismrdquo Hepatobiliary Surgeryand Nutrition vol 3 no 3 pp 126ndash139 2014

[18] A Piskunov Z Al Tanoury and C Rochette-Egly ldquoNuclear andextra-nuclear effects of retinoid acid receptors how they areinterconnectedrdquo in The Biochemistry of Retinoic Acid ReceptorsI Structure Activation and Function at theMolecular Level vol70 of Subcellular Biochemistry pp 103ndash127 Springer DordrechtThe Netherlands 2014


[19] R M Evans and D J Mangelsdorf ldquoNuclear receptors RXRand the big bangrdquo Cell vol 157 no 1 pp 255ndash266 2014

[20] J von Lintig ldquoProvitamin A metabolism and functions inmammalian biologyrdquo American Journal of Clinical Nutritionvol 96 no 5 pp 1234Sndash1244S 2012

[21] T Moore ldquoVitamin A and carotene VI The conversion ofcarotene to vitamin A in vivordquo Biochemical Journal vol 24 no3 pp 692ndash702 1930

[22] K Palczewski ldquoG protein-coupled receptor rhodopsinrdquoAnnualReview of Biochemistry vol 75 pp 743ndash767 2006

[23] J von Lintig P D Kiser M Golczak and K Palczewski ldquoThebiochemical and structural basis for trans-to-cis isomerizationof retinoids in the chemistry of visionrdquo Trends in BiochemicalSciences vol 35 no 7 pp 400ndash410 2010

[24] J A Olson and D Gunning ldquoThe storage form of vitamin A inrat liver cellsrdquo Journal of Nutrition vol 113 no 11 pp 2184ndash21911983

[25] E Reboul ldquoAbsorption of vitamin A and carotenoids by theenterocyte focus on transport proteinsrdquo Nutrients vol 5 no9 pp 3563ndash3581 2013

[26] P Borel ldquoFactors affecting intestinal absorption of highly lipo-philic foodmicroconstituents (fat-soluble vitamins carotenoidsand phytosterols)rdquoClinical Chemistry and LaboratoryMedicinevol 41 no 8 pp 979ndash994 2003

[27] V Tyssandier E Reboul J-F Dumas et al ldquoProcessing ofvegetable-borne carotenoids in the human stomach and duo-denumrdquo American Journal of PhysiologymdashGastrointestinal andLiver Physiology vol 284 no 6 pp G913ndashG923 2003

[28] P Borel B PasquierM Armand et al ldquoProcessing of vitamin Aand E in the human gastrointestinal tractrdquo American Journal ofPhysiologymdashGastrointestinal and Liver Physiology vol 280 no1 pp G95ndashG103 2001

[29] F Carriere J A Barrowman R Verger and R Laugier ldquoSecre-tion and contribution to lipolysis of gastric and pancreaticlipases during a test meal in humansrdquoGastroenterology vol 105no 3 pp 876ndash888 1993

[30] D Lombardo and O Guy ldquoStudies on the substrate specificityof a carboxyl ester hydrolase from human pancreatic juice IIAction on cholesterol esters and lipid-soluble vitamin estersrdquoBiochimica et Biophysica Acta vol 611 no 1 pp 147ndash155 1980

[31] H A Zahalka S C Cheng G W Burton and K U IngoldldquoHydrolysis of stereoisomeric alpha-tocopheryl acetates cat-alyzed by bovine cholesterol esteraserdquo Biochimica et BiophysicaActamdashLipids and Lipid Metabolism vol 921 no 3 pp 481ndash4851987

[32] C Lauridsen M S Hedemann and S K Jensen ldquoHydrolysisof tocopheryl and retinyl esters by porcine carboxyl esterhydrolase is affected by their carboxylate moiety and bile acidsrdquoJournal of Nutritional Biochemistry vol 12 no 4 pp 219ndash2242001

[33] B Sivakumar and V Reddy ldquoAbsorption of labelled vitamin Ain children during infectionrdquo British Journal of Nutrition vol27 no 2 pp 299ndash304 1972

[34] M E OrsquoNeill and D I Thurnham ldquoIntestinal absorption of120573-carotene lycopene and lutein in men and women followinga standard meal response curves in the triacylglycerol-richlipoprotein fractionrdquo British Journal of Nutrition vol 79 no 2pp 149ndash159 1998

[35] J A Novotny S R Dueker L A Zech and A J Clifford ldquoCom-partmental analysis of the dynamics of 120573-carotene metabolismin an adult volunteerrdquo Journal of Lipid Research vol 36 no 8pp 1825ndash1838 1995

[36] T van Vliet W H P Schreurs and H van den Berg ldquoIntestinal120573-carotene absorption and cleavage in men response of 120573-carotene and retinyl esters in the triglyceride-rich lipoproteinfraction after a single oral dose of 120573-carotenerdquo The AmericanJournal of Clinical Nutrition vol 62 no 1 pp 110ndash116 1995

[37] M van Lieshout C E West and R B van Breemen ldquoIsotopictracer techniques for studying the bioavailability and bioefficacyof dietary carotenoids particularly 120573-carotene in humans areviewrdquo The American Journal of Clinical Nutrition vol 77 no1 pp 12ndash28 2003

[38] R M Faulks D J Hart P D G Wilson K J Scott andS Southon ldquoAbsorption of all-trans and 9-cis 120573-carotene inhuman ileostomy volunteersrdquo Clinical Science vol 93 no 6 pp585ndash591 1997

[39] T C Quick and D E Ong ldquoVitamin A metabolism in thehuman intestinal Caco-2 cell linerdquo Biochemistry vol 29 no 50pp 11116ndash11123 1990

[40] R Kawaguchi J Yu J Honda et al ldquoA membrane receptor forretinol binding protein mediates cellular uptake of vitamin ArdquoScience vol 315 no 5813 pp 820ndash825 2007

[41] D Hollander and P E Ruble Jr ldquobeta-carotene intestinalabsorption bile fatty acid pH and flow rate effects on trans-portrdquo The American Journal of Physiology vol 235 no 6 ppE686ndash691 1978

[42] P Sauvant N Mekki M Charbonnier H Portugal D Laironand P Borel ldquoAmounts and types of fatty acids in meals affectthe pattern of retinoids secreted in human chylomicrons aftera high-dose preformed vitamin A intakerdquoMetabolism Clinicaland Experimental vol 52 no 4 pp 514ndash519 2003

[43] J J M Castenmiller and C E West ldquoBioavailability andbioconversion of carotenoidsrdquo Annual Review of Nutrition vol18 pp 19ndash38 1998

[44] J L Napoli ldquoRetinoic acid biosynthesis and metabolismrdquoFASEB Journal vol 10 no 9 pp 993ndash1001 1996

[45] N Noy ldquoRetinoid-binding proteins mediators of retinoidactionrdquo Biochemical Journal vol 348 no 3 pp 481ndash495 2000

[46] R H Zetterstrom ldquoLocalization of cellular retinoid-bindingproteins suggests specific roles for retinoids in the adult centralnervous systemrdquo Neuroscience vol 62 no 3 pp 899ndash918 1994

[47] R Blomhoff and H K Blomhoff ldquoOverview of retinoidmetabolism and functionrdquo Journal of Neurobiology vol 66 no7 pp 606ndash630 2006

[48] M N Vergara Y Arsenijevic and K del Rio-Tsonis ldquoCNSregeneration a morphogenrsquos talerdquo Journal of Neurobiology vol64 no 4 pp 491ndash507 2005

[49] P McCaffery and U C Drager ldquoHigh levels of a retinoic acid-generating dehydrogenase in the meso-telencephalic dopaminesystemrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 91 no 16 pp 7772ndash7776 1994

[50] W Krezel N Ghyselinck T A Samad et al ldquoImpaired locomo-tion and dopamine signaling in retinoid receptor mutant micerdquoScience vol 279 no 5352 pp 863ndash867 1998

[51] S Urano Y Inomori T Sugawara et al ldquoVitamin E inhibitionof retinol-induced hemolysis and membrane-stabilizing behav-iorrdquo Journal of Biological Chemistry vol 267 no 26 pp 18365ndash18370 1992

[52] S Krishnamurthy T George and N J Bai ldquoHydroxy radicalinvolvement in retinol hemolysis of human erythrocytes invitrordquo Indian Journal of Biochemistry and Biophysics vol 21 no6 pp 397ndash399 1984


[53] AH Goodall D Fisher and J A Lucy ldquoCell fusion haemolysisandmitochondrial swelling induced by retinol and derivativesrdquoBiochimica et Biophysica Acta vol 595 no 1 pp 9ndash14 1980

[54] C J Hogan J S Wiley and T Billington ldquoIntravascularhaemolysis complicating treatment of acute promyelocyticleukaemia with all-trans retinoic acid (ATRA)rdquo Australian andNew Zealand Journal of Medicine vol 27 no 4 pp 450ndash4511997

[55] M P Rigobello G Scutari A Friso E Barzon S Artusiand A Bindoli ldquoMitochondrial permeability transition andrelease of cytochrome c induced by retinoic acidsrdquo BiochemicalPharmacology vol 58 no 4 pp 665ndash670 1999

[56] D R Green L Galluzzi and G Kroemer ldquoMetabolic control ofcell deathrdquo Science vol 345 no 6203 Article ID 1250256 2014

[57] F KlamtMR deOliveira and J C FMoreira ldquoRetinol inducespermeability transition and cytochrome c release from rat livermitochondriardquo Biochimica et Biophysica Acta General Subjectsvol 1726 no 1 pp 14ndash20 2005

[58] F Klamt F dal-Pizzol D P Gelain et al ldquoVitamin A treatmentinduces apoptosis through an oxidant-dependent activation ofthe mitochondrial pathwayrdquo Cell Biology International vol 32no 1 pp 100ndash106 2008

[59] F S G Silva M P C Ribeiro M S Santos P Rocha-PereiraA Santos-Silva and J B A Custodio ldquoAcitretin affects bioener-getics of liver mitochondria and promotes mitochondrial per-meability transition potential mechanisms of hepatotoxicityrdquoToxicology vol 306 pp 93ndash100 2013

[60] O Sawada L Perusek H Kohno et al ldquoAll-trans-retinalinduces Bax activation via DNA damage to mediate retinal cellapoptosisrdquo Experimental Eye Research vol 123 pp 27ndash36 2014

[61] AMaeda TMaedaMGolczak andK Palczewski ldquoRetinopa-thy in mice induced by disrupted all-trans-retinal clearancerdquoJournal of Biological Chemistry vol 283 no 39 pp 26684ndash26693 2008

[62] H El Hajj B Khalil B Ghandour et al ldquoPreclinical effi-cacy of the synthetic retinoid ST1926 for treating adult T-cellleukemialymphomardquo Blood vol 124 no 13 pp 2072ndash20802014

[63] M R de Oliveira R B Silvestrin T Mello E Souza and J CF Moreira ldquoOxidative stress in the hippocampus anxiety-likebehavior and decreased locomotory and exploratory activity ofadult rats effects of sub acute vitamin A supplementation attherapeutic dosesrdquoNeuroToxicology vol 28 no 6 pp 1191ndash11992007

[64] M R de Oliveira M A de Bittencourt Pasquali R B Sil-vestrin T Mello e Souza and J C F Moreira ldquoVitamin Asupplementation induces a prooxidative state in the striatumand impairs locomotory and exploratory activity of adult ratsrdquoBrain Research vol 1169 no 1 pp 112ndash119 2007

[65] M R de Oliveira and J C F Moreira ldquoAcute and chronicvitamin A supplementation at therapeutic doses induces oxida-tive stress in submitochondrial particles isolated from cerebralcortex and cerebellum of adult ratsrdquo Toxicology Letters vol 173no 3 pp 145ndash150 2007

[66] M R de Oliveira R B Silvestrin T Mello e Souza and J CF Moreira ldquoTherapeutic vitamin A doses increase the levelsof markers of oxidative insult in substantia nigra and decreaselocomotory and exploratory activity in rats after acute andchronic supplementationrdquo Neurochemical Research vol 33 no3 pp 378ndash383 2008

[67] M R de Oliveira M W S Oliveira G A Behr M L MHoff R F da Rocha and J C F Moreira ldquoEvaluation of the

effects of vitamin A supplementation on adult rat substan-tia nigra and striatum redox and bioenergetic states mito-chondrial impairment increased 3-nitrotyrosine and alpha-synuclein but decreased D2 receptor contentsrdquo Progress inNeuro-Psychopharmacology and Biological Psychiatry vol 33no 2 pp 353ndash362 2009

[68] M R De Oliveira M W S Oliveira R F Da Rocha and JC F Moreira ldquoVitamin A supplementation at pharmacologicaldoses induces nitrosative stress on the hypothalamus of adultWistar ratsrdquo Chemico-Biological Interactions vol 180 no 3 pp407ndash413 2009

[69] M R de Oliveira M W S Oliveira G A Behr and JC F Moreira ldquoVitamin A supplementation at clinical dosesinduces a dysfunction in the redox and bioenergetics statesbut did change neither caspases activities nor TNF-120572 levels inthe frontal cortex of adult Wistar ratsrdquo Journal of PsychiatricResearch vol 43 no 8 pp 754ndash762 2009

[70] M R deOliveira R F da Rocha and J C FMoreira ldquoIncreasedsusceptibility of mitochondria isolated from frontal cortexand hippocampus of vitamin A-treated rats to non-aggregatedamyloid-120573 peptides 1ndash40 and 1ndash42rdquoActa Neuropsychiatrica vol24 no 2 pp 101ndash108 2012

[71] M R de Oliveira R F da Rocha L Stertz et al ldquoTotaland mitochondrial nitrosative stress decreased brain-derivedneurotrophic factor (BDNF) levels and glutamate uptake andevidence of endoplasmic reticulum stress in the hippocampusof vitamin A-treated ratsrdquo Neurochemical Research vol 36 no3 pp 506ndash517 2011

[72] M R de Oliveira M W Soares Oliveira M L Muller Hoff GA Behr R F da Rocha and J C Fonseca Moreira ldquoEvaluationof redox and bioenergetics states in the liver of vitamin A-treated ratsrdquo European Journal of Pharmacology vol 610 no 1ndash3 pp 99ndash105 2009

[73] M R de Oliveira M W S Oliveira R Lorenzi R Fagundes daRocha and J C Fonseca Moreira ldquoShort-term vitamin A sup-plementation at therapeutic doses induces a pro-oxidative statein the hepatic environment and facilitates calcium-ion-inducedoxidative stress in rat liver mitochondria independently frompermeability transition pore formation detrimental effects ofvitamin A supplementation on rat liver redox and bioenergeticstates homeostasisrdquo Cell Biology and Toxicology vol 25 no 6pp 545ndash560 2009

[74] R F da Rocha M R de Oliveira P Schonhofen C E SchnorrF Dal Pizzol and J C FMoreira ldquoLong-term vitaminA supple-mentation at therapeutic doses inducesmitochondrial electronstransfer chain (METC) impairment and increased mitochon-drial membrane-enriched fraction (MMEF) 3-nitrotyrosine onrat heartrdquo Free Radical Research vol 44 no 5 pp 505ndash512 2010

[75] M A de Bittencourt Pasquali M R de Oliveira M Ade Bastiani et al ldquoL-NAME co-treatment prevent oxidativedamage in the lung of adult Wistar rats treated with vitamin AsupplementationrdquoCell Biochemistry and Function vol 30 no 3pp 256ndash263 2012

[76] M R de Oliveira and J C FMoreira ldquoImpaired redox state andrespiratory chain enzyme activities in the cerebellum of vitaminA-treated ratsrdquo Toxicology vol 253 no 1ndash3 pp 125ndash130 2008

[77] M R de Oliveira R F da Rocha C E Schnorr and J C FMoreira ldquoL-NAME cotreatment did prevent neither mitochon-drial impairment nor behavioral abnormalities in adult Wistarrats treated with vitaminA supplementationrdquo Fundamental andClinical Pharmacology vol 26 no 4 pp 513ndash529 2012


[78] M R de Oliveira R Lorenzi C E Schnorr M Morrone andJ C F Moreira ldquoIncreased 3-nitrotyrosine levels in mitochon-drial membranes and impaired respiratory chain activity inbrain regions of adult female rats submitted to daily vitamin Asupplementation for 2 monthsrdquo Brain Research Bulletin vol 86no 3-4 pp 246ndash253 2011

[79] V G Grivennikova and A D Vinogradov ldquoGeneration ofsuperoxide by the mitochondrial complex Irdquo Biochimica etBiophysica Acta vol 1757 no 5-6 pp 553ndash561 2006

[80] A Y Andreyev Y E Kushnareva andAA Starkov ldquoMitochon-drial metabolism of reactive oxygen speciesrdquo Biochemistry vol70 no 2 pp 200ndash214 2005

[81] M R de Oliveira M W S Oliveira and J C F MoreiraldquoPharmacological doses of vitaminA increase caspase-3 activityselectively in cerebral cortexrdquo Fundamental amp Clinical Pharma-cology vol 24 no 4 pp 445ndash450 2010

[82] R Radi ldquoPeroxynitrite a stealthy biological oxidantrdquo TheJournal of Biological Chemistry vol 288 no 37 pp 26464ndash26472 2013

[83] S Carballal S Bartesaghi and R Radi ldquoKinetic and mechanis-tic considerations to assess the biological fate of peroxynitriterdquoBiochimica et BiophysicaActa vol 1840 no 2 pp 768ndash780 2014

[84] B I Giasson J E Duda I V J Murray et al ldquoOxidative damagelinked to neurodegeneration by selective 120572-synuclein nitrationin synucleinopathy lesionsrdquo Science vol 290 no 5493 pp 985ndash989 2000

[85] J M Souza B I Giasson Q Chen V M-Y Lee and HIschiropoulos ldquoDityrosine cross-linking promotes formationof stable 120572-synuclein polymers Implication of nitrative andoxidative stress in the pathogenesis of neurodegenerative synu-cleinopathiesrdquoThe Journal of Biological Chemistry vol 275 no24 pp 18344ndash18349 2000

[86] J P Eiserich A G Estevez T V Bamberg P H Chumley JS Beckman and B A Freeman ldquoMicrotubule dysfunction byposttranslational nitrotyrosination of 120572- tubulin a nitric oxide-dependent mechanism of cellular injuryrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 96 no 11 pp 6365ndash6370 1999

[87] B Halliwell ldquoOxidative stress and neurodegeneration whereare we nowrdquo Journal of Neurochemistry vol 97 no 6 pp 1634ndash1658 2006

[88] A Bir O Sen S Anand et al ldquo120572-synuclein-induced mito-chondrial dysfunction in isolated preparation and intact cellsimplications in the pathogenesis of Parkinsonrsquos diseaserdquo Journalof Neurochemistry vol 131 no 6 pp 868ndash877 2014

[89] M Robotta H R Gerding A Vogel et al ldquoAlpha-synucleinbinds to the inner membrane of mitochondria in an 120572-helicalconformationrdquo ChemBioChem vol 15 no 17 pp 2499ndash25022014

[90] M R de Oliveira R F da Rocha M A D B Pasquali and JC F Moreira ldquoThe effects of vitamin A supplementation for 3months on adult rat nigrostriatal axis increased monoamineoxidase enzyme activity mitochondrial redox dysfunctionincreased 120573-amyloid1-40 peptide and TNF-120572 contents andsusceptibility of mitochondria to an in vitro H

2

O2

challengerdquoBrain Research Bulletin vol 87 no 4-5 pp 432ndash444 2012

[91] D E Edmondson ldquoHydrogen peroxide produced bymitochon-drial monoamine oxidase catalysis biological implicationsrdquoCurrent Pharmaceutical Design vol 20 no 2 pp 155ndash160 2014

[92] A Boveris and B Chance ldquoThe mitochondrial generation ofhydrogen peroxiderdquoBiochemical Journal vol 134 no 3 pp 707ndash716 1973

[93] E A Veal A M Day and B A Morgan ldquoHydrogen peroxidesensing and signalingrdquo Molecular Cell vol 26 no 1 pp 1ndash142007

[94] M Reth ldquoHydrogen peroxide as second messenger in lympho-cyte activationrdquoNature Immunology vol 3 no 12 pp 1129ndash11342002

[95] S G Rhee S W Kang W Jeong T-S Chang K-S Yangand H A Woo ldquoIntracellular messenger function of hydrogenperoxide and its regulation by peroxiredoxinsrdquoCurrent Opinionin Cell Biology vol 17 no 2 pp 183ndash189 2005

[96] J R Stone and S Yang ldquoHydrogen peroxide a signalingmessengerrdquo Antioxidants and Redox Signaling vol 8 no 3-4pp 243ndash270 2006

[97] B Halliwell ldquoFree radicals and antioxidants updating a per-sonal viewrdquo Nutrition Reviews vol 70 no 5 pp 257ndash265 2012

[98] Y Kono and I Fridovich ldquoSuperoxide radical inhibits catalaserdquoThe Journal of Biological Chemistry vol 257 no 10 pp 5751ndash5754 1982

[99] D F A R Dourado P A Fernandes and M J Ramos ldquoMam-malian cytosolic glutathione transferasesrdquo Current Protein andPeptide Science vol 9 no 4 pp 325ndash337 2008

[100] K Rashid K Sinha and P C Sil ldquoAn update on oxidativestress-mediated organ pathophysiologyrdquo Food and ChemicalToxicology vol 62 pp 584ndash600 2013

[101] T Szkudelski M Okulicz I Bialik and K Szkudelska ldquoTheinfluence of fasting on liver sulfhydryl groups glutathioneperoxidase and glutathione-S-transferase activities in the ratrdquoJournal of Physiology and Biochemistry vol 60 no 1 pp 1ndash62004

[102] J Sian-Hulsmann S Mandel M B H Youdim and P RiedererldquoThe relevance of iron in the pathogenesis of Parkinsonrsquosdiseaserdquo Journal of Neurochemistry vol 118 no 6 pp 939ndash9572011

[103] A Friedman J Galazka-Friedman and D Koziorowski ldquoIronas a cause of Parkinson diseasemdasha myth or a well establishedhypothesisrdquo Parkinsonism and Related Disorders vol 15 sup-plement 3 pp S212ndashS214 2009

[104] M Politis ldquoNeuroimaging in Parkinson disease from researchsetting to clinical practicerdquo Nature Reviews Neurology vol 10no 12 pp 708ndash722 2014

[105] J-A Girault ldquoSignaling in striatal neurons the phosphopro-teins of reward addiction and dyskinesiardquo Progress in Molec-ular Biology and Translational Science vol 106 pp 33ndash62 2012

[106] M R Duchen ldquoMitochondria and Ca2+ in cell physiology andpathophysiologyrdquo Cell Calcium vol 28 no 5-6 pp 339ndash3482000

[107] L Galluzzi J M Bravo-San Pedro andG Kroemer ldquoOrganelle-specific initiation of cell deathrdquo Nature Cell Biology vol 16 no8 pp 728ndash736 2014

[108] D-F Suen K L Norris and R J Youle ldquoMitochondrialdynamics and apoptosisrdquo Genes amp Development vol 22 no 12pp 1577ndash1590 2008

[109] M Manczak T S Anekonda E Henson B S Park JQuinn and P H Reddy ldquoMitochondria are a direct site ofA120573 accumulation in Alzheimerrsquos disease neurons implicationsfor free radical generation and oxidative damage in diseaseprogressionrdquoHumanMolecular Genetics vol 15 no 9 pp 1437ndash1449 2006

[110] X Chen and S D Yan ldquoMitochondrial A120573 a potential cause ofmetabolic dysfunction in Alzheimerrsquos diseaserdquo IUBMB Life vol58 no 12 pp 686ndash694 2006


[111] P F Pavlov C H Petersen E Glaser and M AnkarcronaldquoMitochondrial accumulation of APP and A120573 significancefor Alzheimer disease pathogenesisrdquo Journal of Cellular andMolecular Medicine vol 13 no 10 pp 4137ndash4145 2009

[112] H Du L Guo F Fang et al ldquoCyclophilin D deficiency attenu-ates mitochondrial and neuronal perturbation and ameliorateslearning and memory in Alzheimerrsquos diseaserdquoNature Medicinevol 14 no 10 pp 1097ndash1105 2008

[113] J Yao R W Irwin L Zhao J Nilsen R T Hamilton andR D Brinton ldquoMitochondrial bioenergetic deficit precedesAlzheimerrsquos pathology in female mouse model of Alzheimerrsquosdiseaserdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 106 no 34 pp 14670ndash14675 2009

[114] V S Boyce and L M Mendell ldquoNeurotrophins and spinalcircuit functionrdquo Frontiers in Neural Circuits vol 8 article 592014

[115] B Lu G Nagappan and Y Lu ldquoBDNF and synaptic plasticitycognitive function and dysfunctionrdquo in Neurotrophic Factorsvol 220 of Handbook of Experimental Pharmacology pp 223ndash250 Springer 2014

[116] M M Poo ldquoNeurotrophins as synaptic modulatorsrdquo NatureReviews Neuroscience vol 2 no 1 pp 24ndash32 2001

[117] J Burkhalter H Fiumelli I Allaman J-Y Chatton and J-LMartin ldquoBrain-derived neurotrophic factor stimulates energymetabolism in developing cortical neuronsrdquo Journal of Neuro-science vol 23 no 23 pp 8212ndash8220 2003

[118] AMarkham I Cameron P Franklin andM Spedding ldquoBDNFincreases rat brain mitochondrial respiratory coupling at com-plex I but not complex IIrdquo European Journal of Neurosciencevol 20 no 5 pp 1189ndash1196 2004

[119] J D Bremner N Fani A Ashraf et al ldquoFunctional brainimaging alterations in acne patients treated with isotretinoinrdquoAmerican Journal of Psychiatry vol 162 no 5 pp 983ndash991 2005

[120] S E Wolverton and J C Harper ldquoImportant controversiesassociated with isotretinoin therapy for acnerdquoAmerican Journalof Clinical Dermatology vol 14 no 2 pp 71ndash76 2013

[121] R Ballester Sanchez B De Unamuno Bustos A Agustı Mejıasand M I Febrer Bosch ldquoIncrease in creatine phosphokinaseand a suicide attempt during isotretinoin treatmentrdquo Anales dePediatrıa vol 76 no 6 pp 365ndash366 2012

[122] P Saitta P Keehan J Yousif B V Way S Grekin and R Bran-caccio ldquoAn update on the presence of psychiatric comorbiditiesin acne patients part 2 depression anxiety and suiciderdquo Cutisvol 88 no 2 pp 92ndash97 2011

[123] D K Wysowski M Pitts and J Beitz ldquoAn analysis of reportsof depression and suicide in patients treated with isotretinoinrdquoJournal of the American Academy of Dermatology vol 45 no 4pp 515ndash519 2001

[124] Z Nevoralova and D Dvorakova ldquoMood changes depressionand suicide risk during isotretinoin treatment a prospectivestudyrdquo International Journal of Dermatology vol 52 no 2 pp163ndash168 2013

[125] G Bjelakovic D Nikolova L L Gluud R G Simonettiand C Gluud ldquoMortality in randomized trials of antioxidantsupplements for primary and secondary prevention systematicreview and meta-analysisrdquo Journal of the American MedicalAssociation vol 297 no 8 pp 842ndash857 2007

[126] G Bjelakovic D Nikolova and C Gluud ldquoMeta-regressionanalyses meta-analyses and trial sequential analyses of theeffects of supplementation with beta-carotene vitamin A andvitamin E singly or in different combinations on all-cause

mortality do we have evidence for lack of harmrdquo PloS one vol8 no 9 Article ID e74558 2013

[127] G Bjelakovic D Nikolova and C Gluud ldquoAntioxidant supple-ments and mortalityrdquo Current Opinion and Clinical Nutritionand Metabolic Care vol 17 no 1 pp 40ndash44 2014

[128] J H Humphrey P J Iliff E T Marinda et al ldquoEffects of a singlelarge dose of vitamin A given during the postpartum period toHIV-positive women and their infants on child HIV infectionHIV-free survival and mortalityrdquo Journal of Infectious Diseasesvol 193 no 6 pp 860ndash871 2006

[129] C E Orfanos C C Zouboulis B Almond-Roesler and C CGeilen ldquoCurrent use and future potential role of retinoids indermatologyrdquo Drugs vol 53 no 3 pp 358ndash388 1997

[130] J Li and A S Lee ldquoStress induction of GRP78BiP and its rolein cancerrdquo Current Molecular Medicine vol 6 no 1 pp 45ndash542006

[131] T Gutierrez and T Simmen ldquoEndoplasmic reticulum chap-erones and oxidoreductases critical regulators of tumor cellsurvival and immunorecognitionrdquo Frontiers in Oncology vol 4article 291 2014

[132] V Borutaite R Morkuniene and G C Brown ldquoRelease ofcytochrome c from heart mitochondria is induced by highCa2+ and peroxynitrite and is responsible for Ca2+-inducedinhibition of substrate oxidationrdquoBiochimica et BiophysicaActavol 1453 no 1 pp 41ndash48 1999

[133] J Crandall Y Sakai J Zhang et al ldquo13-cis-retinoic acid sup-presses hippocampal cell division and hippocampal-dependentlearning in micerdquo Proceedings of the National Academy ofSciences of the United States of America vol 101 no 14 pp 5111ndash5116 2004

[134] Y Sakai J E Crandall J Brodsky and P McCaffery ldquo13-cisretinoic acid (accutane) suppresses hippocampal cell survival inmicerdquoAnnals of the New York Academy of Sciences vol 1021 pp436ndash440 2004

[135] C Guruvayoorappan C R Pradeep and G Kuttan ldquo13-cis-Retinoic acid induces apoptosis by modulating caspase-3 bcl-2 and p53 gene expression and regulates the activation oftranscription factors in B16F-10 melanoma cellsrdquo Journal ofEnvironmental Pathology Toxicology and Oncology vol 27 no3 pp 197ndash207 2008

[136] D M Bannerman M Grubb R M J Deacon B K Yee JFeldon and J N P Rawlins ldquoVentral hippocampal lesions affectanxiety but not spatial learningrdquo Behavioural Brain Researchvol 139 no 1-2 pp 197ndash213 2003

[137] D M Bannerman J N P Rawlins S B McHugh et alldquoRegional dissociationswithin the hippocampusmdashmemory andanxietyrdquo Neuroscience and Biobehavioral Reviews vol 28 no 3pp 273ndash283 2004

[138] R M J Deacon and J N P Rawlins ldquoHippocampal lesionsspecies-typical behaviours and anxiety in micerdquo BehaviouralBrain Research vol 156 no 2 pp 241ndash249 2005

[139] J Lotharius and P Brundin ldquoPathogenesis of Parkinsonrsquos dis-ease dopamine vesicles and alpha-synucleinrdquo Nature reviewsNeuroscience vol 3 no 12 pp 932ndash942 2002

[140] L E Salminen and R H Paul ldquoOxidative stress and geneticmarkers of suboptimal antioxidant defense in the aging brain atheoretical reviewrdquo Reviews in the Neurosciences vol 25 no 6pp 805ndash819 2014

[141] G S Omenn G E Goodman M D Thornquist et al ldquoRiskfactors for lung cancer and for intervention effects in CARETthe beta-carotene and retinol efficacy trialrdquo Journal of theNational Cancer Institute vol 88 no 21 pp 1550ndash1559 1996

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014


MEDIATORSINFLAMMATION

of


Behavioural Neurology

EndocrinologyInternational Journal of



Disease Markers


BioMed Research International

OncologyJournal of



Oxidative Medicine and Cellular Longevity


PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of



Computational and Mathematical Methods in Medicine

OphthalmologyJournal of


Diabetes ResearchJournal of



Research and TreatmentAIDS


Gastroenterology Research and Practice


Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom


all retinoids are formed by a 120573-ionone ring and a polyun-saturated side chain and a chemical group varying fromalcohol to carboxylic acid or ester as mentioned above Thepresence of conjugated double bonds is noteworthy whichmay be in either trans-configuration or cis-configuration inthe molecule of retinoids [14 15] Such chemical structuredecreases its solubility in aqueous environments

Vitamin A (retinol) and its derivatives the retinoidsparticipate in a myriad of biological processes during animallife from development to adulthood and aging Controlof cell proliferation differentiation induction of cell deaththrough apoptosis formation and shaping of the embryoorganogenesis and tissue homeostasis depend on physi-ological concentrations of vitamin A to occur adequately[9 14ndash16] Among retinoids all-trans retinoic acid is betterstudied because it is the most biologically potent vitamin Aderivative [9 12 14 15] Vitamin A and retinoids may exerttheir functions by binding to nuclear receptors (genomicaction induction or repression of the expression of targetgenes) or though regulation of signaling pathway dependenton phosphorylation of specific targets (nongenomic actiona rapid way to regulate cell events through the action ofprotein kinases and phosphatases) that culminate in a cellularresponse to such stimulus [12 14 15 17ndash19]

VitaminAmay be obtained from both vegetal and animaldiets 120573-Carotene (an isoprenoid compound) is convertedto two molecules of all-trans-retinal by centric oxidativecleavage and all-trans-retinal is reduced to all-trans-retinolwhichmay be esterified and stored in large amounts in tissuesas liver lung and fat [12 20 21] In the eyes retinoids areconverted to 11-cis-retinal which is a visual chromophore thatbinds to opsin in order to translate light into an electricalsignal [22 23] Esterified retinol in the form of retinolpalmitate is a major source of vitamin A from diet of animalorigin as for instance liver which stores the excess ofvitamin A [14 15 20 24]

The absorption of fat-soluble micronutrients occurs verysimilarly to that observed in lipids in the upper gastroin-testinal tract [25 26] after dissolution via formation oflipid droplets in both stomach and duodenum [27 28] Theesterified forms of vitamin A (mainly retinol palmitate) arefirstly hydrolyzed in the duodenum and the free form is thenabsorbed by the intestinal mucosa [29] It is suggested thattwo pancreatic enzymes perform such hydrolysis namelycholesterol ester hydrolase and pancreatic lipase [30ndash32]Then the enterocyte will absorb vitamin A and carotenoidswhich are incorporated into micelles with other lipids fromdiet [25 26] It was reported that the efficiency of retinolabsorption is around 75 [33] and 100 [34ndash37] On theother hand the efficiency of 120573-carotene absorption wasestimated to be from 3 to 90 [36ndash38] It was proposed thatenterocytes present a specific retinol transporter that func-tions very efficiently [39 40] The absorption of carotenoidsoccurs mainly through passive diffusion [41]

After enterocyte uptake retinol is esterified by lecithinretinol acyltransferase (LRAT which utilizes phosphatidyl-choline as acyl group donor) and acyl-CoA acyltransferase(ARAT) leading to the formation of retinol palmitateretinol oleate and retinol linoleate among others [25 42]

Carotenoids may follow one of these paths inside entero-cytes stay not metabolized (around 40 of provitamin Acarotenoids) be cleavage generating retinal via the reactionmediated by 120573-carotene-15151015840-monooxygenase or be cleav-age by mitochondrial 120573-carotene-91015840101015840-dioxygenase whichis responsible for the formation of apocarotenoids [43]

In the cytosol of the enterocyte retinol and its derivatives(mainly retinal and retinoic acids) bind to specific proteinscalled cellular retinol-binding protein II (CRBP II) [25]In other cells as for instance the hepatocytes CRBP Iis responsible for free retinol transport Additionally thebinding of retinol to CRBP is necessary to its esterificationby LRAT or ARAT In the hepatocytes esterified retinol andretinal are also transported by CRBP I In the plasma retinolis transported by retinol binding protein (RBP) to generaldistribution to tissues [14 15] Retinol is converted to retinalby either microsomal or cytosolic retinol dehydrogenase(RoDH) isozymes In turn retinal is converted in retinoicacid by cytosolic retinal dehydrogenase (RalDH) [14 15 44]Retinoic acids bind to cellular retinoic acid binding protein(CRABP) in cytosol and it is suggested that this complexmigrates to nucleus to exert its effects through binding tonuclear receptors to retinoic acid (RAR or RXR) [44 45]

Central nervous system (CNS) cells also possess nuclearreceptors CRBPs and CRABPs as well as enzymes necessaryto the local metabolism of vitamin A and derivatives Addi-tionally it has been postulated that retinoids may act througha nongenomic way in different cell types including neurons[46 47]The role of retinoids is not restricted to developmentof CNS It has been shown that retinoids are responsible forsynaptic plasticity of the hippocampus for maintenance ofdopamine signaling inmesolimbic andmesostriatal neuronsand for survival of nigrostriatal dopaminergic neurons [48ndash50]

3 The Relationship of Vitamin A andRetinoids with Biological Membranes

The hydrophobicity of vitamin A and retinoids is a chemicallimiting its distribution in the aqueous compartments ofthe body As mentioned above it is necessary to bind suchmolecules to transport protein to increase its solubilityIndeed vitamin A reacts with hydrophobic environments asfor example biologicalmembranes andmay interferewith itsphysiology by perturbing phospholipid and steroids home-ostasis It was previously demonstrated that retinol inducedhemolysis by penetrating rabbit erythrocytes and disruptingphysical structure of the membranes [51] According to theauthors such effect did not depend on oxidation of retinoland formation of free radicals However it was observedthat cotreatment with vitamin E alleviated hemolysis In thatwork it was suggested that vitamin E did act by decreasingpermeability and fluidity and not through its antioxidantcapacity In other works the authors found that the retinol-induced hemolysis was dependent on hydroxyl radical for-mation [52] Goodall et al demonstrated that retinol andretinoids (retinaldehyde 120572-retinoic acid iso-13-retinol andretinyl acetate) induced cell fusion hemolysis and swelling























2


2











Vitamin A

activity


production



+

H2O2

O2minus∙


uarr MAO





2

Mn-SODconvertsO2

minus∙ toH2

O2


2

O2


O2






2

O2


2

O2


2

O2


2

O2



minus


uarr SOD darr CAT


O2



O2



O2



2

O2



O2


2

O2


2

O2


2

O2




2


2


2


2





2




2


2

O2




2

O2




1ndash40and peptide




Vitamin A

ER stress


leakage

production


A vicious cycle

activity

Substrate oxidation

enzyme activity


stress H2O2


darr BDNF

uarr Electron

uarr MAO enzyme





uarr Mn-SOD





O2











Vitamin A


membranes




uarr Mitochondrial









2

O2

and CaCl2





6 Conclusion




(CaCl2

and H2

O2





Abbreviations




Acknowledgments


References































































































2

O2




























































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of






































2


2











Vitamin A

activity


production



+

H2O2

O2minus∙


uarr MAO





2

Mn-SODconvertsO2

minus∙ toH2

O2


2

O2


O2






2

O2


2

O2


2

O2


2

O2



minus


uarr SOD darr CAT


O2



O2



O2



2

O2



O2


2

O2


2

O2


2

O2




2


2


2


2





2




2


2

O2




2

O2




1ndash40and peptide




Vitamin A

ER stress


leakage

production


A vicious cycle

activity

Substrate oxidation

enzyme activity


stress H2O2


darr BDNF

uarr Electron

uarr MAO enzyme





uarr Mn-SOD





O2











Vitamin A


membranes




uarr Mitochondrial









2

O2

and CaCl2





6 Conclusion




(CaCl2

and H2

O2





Abbreviations




Acknowledgments


References































































































2

O2




























































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of






















2


2











Vitamin A

activity


production



+

H2O2

O2minus∙


uarr MAO





2

Mn-SODconvertsO2

minus∙ toH2

O2


2

O2


O2






2

O2


2

O2


2

O2


2

O2



minus


uarr SOD darr CAT


O2



O2



O2



2

O2



O2


2

O2


2

O2


2

O2




2


2


2


2





2




2


2

O2




2

O2




1ndash40and peptide




Vitamin A

ER stress


leakage

production


A vicious cycle

activity

Substrate oxidation

enzyme activity


stress H2O2


darr BDNF

uarr Electron

uarr MAO enzyme





uarr Mn-SOD





O2











Vitamin A


membranes




uarr Mitochondrial









2

O2

and CaCl2





6 Conclusion




(CaCl2

and H2

O2





Abbreviations




Acknowledgments


References































































































2

O2




























































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of



















Vitamin A

activity


production



+

H2O2

O2minus∙


uarr MAO





2

Mn-SODconvertsO2

minus∙ toH2

O2


2

O2


O2






2

O2


2

O2


2

O2


2

O2



minus


uarr SOD darr CAT


O2



O2



O2



2

O2



O2


2

O2


2

O2


2

O2




2


2


2


2





2




2


2

O2




2

O2




1ndash40and peptide




Vitamin A

ER stress


leakage

production


A vicious cycle

activity

Substrate oxidation

enzyme activity


stress H2O2


darr BDNF

uarr Electron

uarr MAO enzyme





uarr Mn-SOD





O2











Vitamin A


membranes




uarr Mitochondrial









2

O2

and CaCl2





6 Conclusion




(CaCl2

and H2

O2





Abbreviations




Acknowledgments


References































































































2

O2




























































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















minus


uarr SOD darr CAT


O2



O2



O2



2

O2



O2


2

O2


2

O2


2

O2




2


2


2


2





2




2


2

O2




2

O2




1ndash40and peptide




Vitamin A

ER stress


leakage

production


A vicious cycle

activity

Substrate oxidation

enzyme activity


stress H2O2


darr BDNF

uarr Electron

uarr MAO enzyme





uarr Mn-SOD





O2











Vitamin A


membranes




uarr Mitochondrial









2

O2

and CaCl2





6 Conclusion




(CaCl2

and H2

O2





Abbreviations




Acknowledgments


References































































































2

O2




























































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















Vitamin A

ER stress


leakage

production


A vicious cycle

activity

Substrate oxidation

enzyme activity


stress H2O2


darr BDNF

uarr Electron

uarr MAO enzyme





uarr Mn-SOD





O2











Vitamin A


membranes




uarr Mitochondrial









2

O2

and CaCl2





6 Conclusion




(CaCl2

and H2

O2





Abbreviations




Acknowledgments


References































































































2

O2




























































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of



















Vitamin A


membranes




uarr Mitochondrial









2

O2

and CaCl2





6 Conclusion




(CaCl2

and H2

O2





Abbreviations




Acknowledgments


References































































































2

O2




























































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















(CaCl2

and H2

O2





Abbreviations




Acknowledgments


References































































































2

O2




























































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of




























































































2

O2




























































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

























































2

O2




























































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of






























2

O2




























































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of






















































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of





















of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















Documents

Review Article Vitamin A and Retinoids as Mitochondrial Toxicantsdownloads.hindawi.com/journals/omcl/2015/140267.pdf · 2015-11-23 · Vitamin A and Retinoids as Mitochondrial Toxicants