Homocysteine Metabolism: Nutritional Modulation and Impact on … · 2019-09-20 · sulfuration pathway of homocysteine. This degradation pathway involves a two-step pro-cess resulting

Page 234 Alternative Medicine Review ◆ Volume 2, Number 4 ◆ 1997

Copyright©1997 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission

Homocysteine Metabolism: NutritionalModulation and Impact on Health and

DiseaseAlan L. Miller, N.D. and Gregory S. Kelly, N.D.

AbstractInterest and research into the causes and treatment of hyperhomocysteinemia

has increased dramatically in recent years, as increased plasma homocysteine hasjoined smoking, dyslipidemia, hypertension, and obesity as an independent risk factorfor cardiovascular disease. In addition, elevated homocysteine levels have been impli-cated in a number of other clinical conditions, including neural tube defects, spontane-ous abortion, placental abruption, low birth weight, renal failure, rheumatoid arthritis,alcoholism, osteoporosis, neuropsychiatric disorders, non-insulin-dependent diabetes,and complications of diabetes. Homocysteine is an intermediate metabolite of me-thionine metabolism and is itself metabolized by two pathways: the re-methylation path-way, which regenerates methionine, and the trans-sulfuration pathway, which degradeshomocysteine into cysteine and then taurine. Because homocysteine is located at thismetabolic crossroad, it impacts all methyl- and sulfur-group metabolism occurring inthe body. Consequently, elevated levels of homocysteine would be expected to nega-tively impact the biosynthesis of all of the following: S-adenosylmethionine, carnitine,chondroitin sulfates, coenzyme A, coenzyme Q10, creatine, cysteine, dimethylglycine,epinephrine, glucosamine sulfate, glutathione, glycine, melatonin, pantethine, phos-phatidylcholine, phosphatidylserine, serine, and taurine. Nutritional intervention withthe cofactors required for optimal metabolism of the methionine-homocysteine path-ways offers a new, integrated possibility for primary prevention and treatment. Supple-mentation with betaine, vitamin B12, folic acid, and vitamin B6 assists in optimizingmethyl- and sulfur-group metabolism, and might play a significant role in the preventionand treatment of a wide array of clinical conditions.(Alt Med Rev 1997;2(4):234-254)

IntroductionHyperhomocysteinemia has received increasing attention during the past decade and

has joined smoking, dyslipidemia, hypertension, and obesity as an independent risk factor forcardiovascular disease. In addition to its role in cardiovascular disease, increased homocysteinelevels have been implicated in a variety of other clinical conditions, including neural tube de-fects, spontaneous abortion, placental abruption, low birth weight, renal failure, non-insulin-dependent diabetes and complications of diabetes, rheumatoid arthritis, alcoholism, osteoporo-sis, and neuropsychiatric disorders (See Table 1).


Alternative Medicine Review ◆ Volume 2, Number 4 ◆ 1997 Page 235

Studies of healthy men and women in-dicate that certain acquired and genetic deter-minants can impact total plasma homocys-teine. Women tend to have lower basal levelsthan men,1 and neither contraceptives nor hor-mone replacement therapy seem to signifi-cantly alter the levels.2 However, in post-meno-pausal women, hormone replacement therapymight slightly decrease elevated homocysteineconcentrations. No significant lowering effectwas observed in women with low homocys-teine levels.3 Generally, homocysteine concen-trations are significantly higher in postmeno-pausal women than in pre-menopausal women; how-ever, the above-mentionedsex differences in homocys-teine concentrations persisteven in elderly popula-tions.4, 5, 6 The anti-estrogendrug tamoxifen, used in thelong-term treatment ofbreast-cancer patients, is re-ported to decrease ho-mocysteine levels in post-menopausal women withbreast cancer.7 Epidemio-logical evidence has shownhomocysteine levels to be45% lower in westernizedadult black South Africansthan in age-matched whiteadults, revealing racial genetic differences inhomocysteine metabolism.8

Nutrition impacts homocysteine con-centrations in both men and women. Those in-dividuals in the lowest quartiles for serumfolate and vitamin B12 (nutrients which im-pact homocysteine metabolism) have signifi-cantly higher concentrations of homocysteine,and men in the lowest quartile of serum pyri-doxal 5'-phosphate (P5P—the bioactive formof vitamin B6) also have increased homocys-teine concentrations.2

An association between coffeeconsumption and the concentration of total

homocysteine in plasma has been reported. Amarked positive dose-response relationbetween coffee consumption and plasmahomocysteine levels was observed. Therelationship was most marked in males andfemales consuming greater than 8 cups ofcoffee per day. The combination of cigarettesmoking and high coffee intake was associatedwith particularly high homocysteineconcentrations.9

Chronic alcohol ingestion has alsobeen associated with increased homocysteinelevels.10, 11

Homocysteine MetabolismMetabolism of the amino acid me-

thionine, a limiting amino acid in the synthe-sis of many proteins, affects several biochemi-cal pathways involving the production of nu-trients which are essential to the optimal func-tioning of the cardiovascular, skeletal, andnervous systems.

Homocysteine is an intermediate prod-uct of methionine metabolism and is itself me-tabolized by two pathways: the re-methylationpathway, which regenerates methionine, andthe trans-sulfuration pathway, which degrades

Hom

ocysteine

Alcoholism Non-insulin-dependent Diabetes MellitusAlzheimer’s Disease OsteoporosisCognitive Decline Parkinson’s DiseaseCoronary Artery Disease Peripheral Vascular DiseaseDeep Vein Thrombosis Placental AbruptionDepression Renal FailureDiabetic Nephropathy Retinal Vascular OcclusionDiabetic Retinopathy Rheumatoid ArthritisIntermittent Claudication SchizophreniaMultiple Sclerosis Spontaneous AbortionMyocardial Infarction StrokeNeural Tube Defects

Table 1. Conditions Associated with Elevated Levels of Homocysteine



homocysteine into cysteine and then taurine.In essence, the intermediate metabolite ho-mocysteine is located at a critical metaboliccrossroad, and therefore both directly and in-directly impacts all methyl and sulfur groupmetabolism occurring in the body. Experi-ments have demonstrated if high enough lev-els of homocysteine and adenosine accumu-late in the cell, all methylation reactions arecompletely inhibited.12

The re-methylation pathway (see Fig-ure 1) is comprised of two intersecting bio-chemical pathways, and results in the transferof a methyl group (CH

3) to homocysteine by

either methylcobalamin or betaine (trimethyl-glycine). Methylcobalamin originally receivesits methyl group from S-adenosylmethionine(SAM) or 5-methyltetrahydrofolate (5-methylTHF), an active form of folic acid. Af-ter re-methylation, methionine can be re-uti-lized to produce SAM, the body’s “universal

methyl donor,” which participates in severalkey metabolic pathways, including methyla-tion of DNA and myelin, synthesis of carnitine,coenzyme Q10, creatine, epinephrine, mela-tonin, methylcobalamin, and phospha-tidylcholine, as well as phase II methylationdetoxification reactions.

The trans-sulfuration pathway of me-thionine/homocysteine degradation (see Fig-ure 1) produces the amino acids cysteine andtaurine, which are important nutrients for car-diac health, hepatic detoxification, cholesterolexcretion, bile salt formation, and glutathioneproduction. This pathway is dependent on ad-equate dietary intake and hepatic conversionof vitamin B6 into its active form, P5P. Alsonecessary is the amino acid serine, a downlinemetabolite generated from betaine via the ho-mocysteine-remethylation pathway.

METHIONINE

HOMOCYSTEINE

ATP/Mg

SAM

CH3-groupacceptor

SAH

adenosine

Serine

P5P

Cysteine

P5P

Taurine

Betaine

DMG

Glycine

methylcobalamin

cob (II) alaminSAM

5-methyl THF

THF

SAH

methioninesynthase

SAM - S-adenosylmethionineSAH - S-adenosylhomocysteine5-methyl THF - 5-methyltetrahydrofolateTHF - TetrahydrofolateDMG - DimethylglycineP5P - Pyridoxal 5'-phosphate (vitamin B6)

Abbreviations

Figure 1. Homocysteine Metabolism



In addition to 5-methylTHF,methylcobalamin, betaine, and P5P, N-acetylcysteine has been reported to signifi-cantly lower homocysteine levels.13

MethyltetrahydrofolateFolates function as carbon donors in

the synthesis of serine from glycine, directlyin the synthesis of purines and pyrimidinebases, indirectly in the synthesis of transferRNA, and as a methyl donor to createmethylcobalamin which is used for re-methy-lation of homocysteine to methionine. Synthe-sis of the active forms of folic acid is a com-plex process requiring several enzymes, as wellas adequate supplies of niacin, riboflavin 5'-phosphate (R5P), P5P, and serine as cofactors(see Figure 2).

The formation of 5, 10-methylene-tetrahydrofolate (5, 10-methyleneTHF) is ofcentral importance, being the precursor of themetabolically-active 5-methylTHF, which isinvolved in homocysteine metabolism. Foli-nic acid (5-formylTHF), available

supplementally as calcium folinate—alsoknown as leucovorin calcium—is an immedi-ate precursor to 5, 10 methyleneTHF. Folinicacid can correct deficiencies of the active formsof folic acid, is more stable than folic acid,has a longer half-life in the body, and readilycrosses the blood-brain barrier.14

MethylcobalaminAlthough the basic cobalamin mol-

ecule is only synthesized by micro-organisms,all mammalian cells can convert it into the co-enzymes adenosylcobalamin and methylco-balamin. Adenosylcobalamin is the primaryform in cellular tissues, where it is retained inthe mitochondria. Methylcobalamin predomi-nates in blood plasma and certain other bodyfluids, and in cells is found in the cytosol.

Methylcobalamin’s only knownbiological function in humans is in the re-methylation of homocysteine to methionine viathe enzyme methionine synthase. In order tooriginally form methylcobalamin fromcyanocobalamin or other Cob(III)alamin or

INTESTINAL

LUMEN

INTESTINES

Folate(Monoglutamate)

DHF

THF

B3

B3

5'-MTHF

Folinic Acid

LIVER

Folate(Monoglutamate)

B3

DHF

THF

B3

5, 10-METHF

B6 P5'P

5-MTHF

Serine

MTHFR

TISSUES

5-MTHF

5,10-METHF

R5'P AbbreviationsDHF = DihydrofolateTHF = Tetrahydrofolate5,10-METHF = 5, 10-Methylenetetrahydrofolate5-MTHF = 5, Methyltetrahydrofolate MTHFR = Methylenetetrahydrofolate ReductaseP5'P = Pyridoxal 5'-PhosphateR5'P = Riboflavin 5'-Phosphate

Dietary Folates(Polyglutamates)

Figure 2. Absorption and Activation of Folic Acid

Hom

ocysteine



Cob(II)alamin precursors, SAM must beavailable to supply a methyl group. Oncemethylcobalamin is formed, it functions in theregeneration of methionine by transferring itsmethyl group to homocysteine. Methyl-cobalamin can then be regenerated by 5-methylTHF (see Figure 3).

BetaineThe metabolic pathways of betaine,

methionine, methylcobalamin, and 5-methylTHF are interrelated, intersecting at theregeneration of methionine from homocys-teine. Since tetrahydrofolate and its derivativescan only cross the mitochondrial membranevery slowly, regeneration of methionine insidethe mitochondria relies heavily on recovery ofa methyl group from betaine.

Betaine donates one of its three me-thyl groups to homocysteine, via the enzymebetaine:homocysteine methyltransferase, re-sulting in the regeneration of methionine. Af-ter donation of the methyl group, one moleculeof dimethylglycine (DMG) remains. This mol-ecule is oxidized to glycine and two moleculesof formaldehyde by riboflavin-dependent en-zymes. The formaldehyde can combine withtetrahydrofolate within the mitochondria togenerate one of the active forms of folic acid,

methylenetetrahydrofolate,which can be converted to 5-methylTHF. (See Figure 4)

Betaine supplementa-tion has been shown to re-duce homocysteine levelswhile resulting in modestincreases of plasma serineand cysteine levels.15 Thisstimulation of betaine-de-pendent homocysteine re-methylation and the subse-quent decrease in plasmahomocysteine can be main-tained as long as supplemen-tal betaine is taken.16

Pyridoxal 5' -PhosphateP5P is the active coenzyme form of vi-

tamin B6. This cofactor is involved in myriadbiological processes, including the trans-sulfuration pathway of homocysteine. Thisdegradation pathway involves a two-step pro-cess resulting in the formation of cystathio-nine and its subsequent cleavage to cysteine.Both of the enzymes involved, cystathioninesynthase and cystathioninase, require P5P asa cofactor. The first step in the degradation ofhomocysteine, via cystathionine synthase, alsorequires serine, a downstream metabolite ofbetaine.

Once cysteine is generated it can bedirected into several pathways, including syn-thesis of glutathione, acetylCoA, and taurine.There are three known pathways from cysteineto taurine; all require P5P.

Homocysteine’s Impact on KeyNutrients

Because of its central role in sulfur andmethyl group metabolism, elevated levels ofhomocysteine would be expected to negativelyimpact the biosynthesis of each of thefollowing: SAM, carnitine, chondroitinsulfates, coenzyme A, coenzyme Q10,

MethylCobalamin

HomocysteineMethionine

5 - methyl-tetrahydrofolate

Cyanocobalamin(Cob(III)alamin) Cob(II)alamin

Tetrahydrofolate

Cob(I)alamin

SAM SAH

Figure 3. Methylcobalamin Metabolism



creatine, cysteine, dimethylglycine,epinephrine, glucosamine sulfate, glutathione,glycine, melatonin, pantethine, phospha-tidylcholine, phosphatidylserine, serine, andtaurine.

S-AdenosylmethionineMethionine is a component of many

proteins and cannot be manufactured fromother dietary amino acids. It serves as a sourceof available sulfur for the synthesis of both cys-teine and taurine, and, as SAM, it is the mostimportant methyl-group donor in cellular me-tabolism.

SAM is formed by the transfer of anadenosyl group from ATP to the sulfur atomof methionine. This reaction requiresmagnesium as a cofactor. When methyl groupsare transferred from SAM, S-adenosylhomo-cysteine is formed, which is then hydrolyzedto release the adenosine and results in theformation of homocysteine.

SAM is known to be utilized in the syn-thesis of the following compounds: carnitine,coenzyme Q10, creatine, methylcobalaminfrom Cob(III)alamin, 1-methylnicotinamide,N-methyltryptamine, phosphatidylcholine,and polyamines. It is also utilized in numer-ous other methylation reactions, including he-patic phase II detoxification.

CarnitineA trimethylated amino acid roughly

similar in structure to choline, carnitine is acofactor for transformation of free, long-chainfatty acids into acylcarnitines, and theirtransport into the mitochondrial matrix, wherethey undergo beta-oxidation for cellular energyproduction. Mitochondrial fatty acid oxidationis the primary fuel source in heart and skeletalmuscle. Synthesis of carnitine begins with themethylation of the amino acid L-lysine bySAM. Methionine, magnesium, vitamin C,iron, P5P, and niacin, along with the cofactorsresponsible for regenerating SAM from

homocysteine (5-methylTHF, methyl-cobalamin, and betaine) are required foroptimal carnitine synthesis.

A pivotal enzyme in carnitine synthe-sis, betaine aldehyde dehydrogenase is thesame enzyme responsible for synthesis of be-taine from choline. Two recent studies suggestthis enzyme has a preference for choline-be-taine conversion, and choline supplementationmight decrease carnitine synthesis; therefore,it might be of greater benefit to supplementwith betaine rather than its precursor, cho-line.17, 18

Chondroitin Sulfates, GlucosamineSulfate and other SulfatedProteoglycans

Proteoglycans are amino sugars foundin all tissues, but are in the highest concentra-tion in cartilage, tendons, ligaments, synovialfluid, skin, finger- and toenails, heart valves,and the basement membrane of all blood ves-sels. Perhaps the most widely known of theamino sugars are the chondroitin sulfates andglucosamine sulfate.

Chondroitin sulfates are primarilycomposed of alternating residues of N-acetyl-D-galactosamine and D-glucuronate. Sulfateresidues are present on C-4 of the galac-tosamine residues in one type of chondroitinand on C-6 in another. Glucosamine sulfate isa simple molecule composed of glucose, theamino acid glutamine, and a sulfate group.Other sulfated proteoglycans include dermatansulfates, keratan sulfates, and heparin sulfates.

High levels of homocysteine are likelyto negatively impact the formation of thesulfated amino sugars because, although somesulfates are present in the diet, thesulfoxidation of cysteine is an important sourceof sulfate molecules. The sulfoxidationpathway proceeds through the toxicintermediate sulfite and requires molybdenumas a cofactor.

Hom

ocysteine



Coenzyme ACoenzyme A consists of an adenine

nucleotide and phosphopantetheine. Containedwithin the structure of this coenzyme is pan-tothenic acid; however, the reactive compo-nent of the molecule is a sulfhydryl groupwhich is not contained within the vitamin. Inorder to form the sulfhydryl-containing mol-ecule (pantotheine), pantothenic acid mustcombine with cysteamine. Cysteamine isformed through conjugation and decarboxy-lation reactions of cysteine. As was previouslydiscussed, the metabolic stagnation caused byelevated homocysteine levels indicates the

body has sub-optimal levels of cys-teine. Because of this, even in thepresence of adequate levels of pan-tothenic acid, it is possible to haveinadequate biosynthesis of acetylcoenzyme A. The disulfate form ofpantetheine, known as pantethine, asopposed to pantothenic acid, by-passes cysteine conjugation and de-carboxylation. This might accountfor some of the clinical benefits seenwith pantethine supplementationwhich have not been reproducedwith supplementation of pan-tothenic acid.

Coenzyme Q10Coenzyme Q10 (CoQ10) is a

fat-soluble quinone occurring in themitochondria of every cell. The pri-mary biochemical action of CoQ10is as a cofactor in the electron trans-port chain, the biochemical pathwayresponsible for generating adenos-ine triphosphate (ATP). Since mostcellular functions are dependent onan adequate supply of ATP, CoQ10is essential for the health of virtu-ally all human tissues and organs.

Biosynthesis of CoQ10 beginswith the amino acid tyrosine. Pantothenic acid,P5P, and vitamin C are all required for the ini-tial steps in its synthesis. An isoprenyl sidechain from farnesyl diphosphate, an interme-diate in cholesterol synthesis, is then added.In two of the final steps in the synthesis ofCoQ10, methyl groups are provided by SAM.Adequate dietary methionine and a sufficientsupply of the nutrients required for re-methy-lation of homocysteine to methionine (5-methylTHF, methylcobalamin, and betaine)are required to generate sufficient SAM foroptimal synthesis of CoQ10.

Choline

B2

DMG

B2

Sarcosine

Glycine Serine

B2

B6B6

Betaine Aldehyde

B3

Betaine

Homocysteine

Phosphatidyl serine

Tetrahydrofolate

Methylenetetrahydro-

folate

Phosphatidyl choline

Phosphatidyl dimethylethanolamine

Phosphatidylethanolamine

Phosphatidyl methyl ethanolamineMethionine

Formaldehyde

SAM

SAM

SAM

Mg++

MN2+

Figure 4. Betaine / Phosphatidylcholine Loop



CreatineIn humans, over 95% of total creatine

content is located in skeletal muscle, of whichapproximately one-third is in its free form ascreatine, also known as methylguani-dinoacetic acid, while the remainder is presentin a phosphorylated form as creatine phosphate(also called phosphocreatine). Creatine phos-phate is utilized within skeletal muscle for stor-ing high energy phosphate bonds.

Creatine is formed in the liver, kidney,and pancreas by the combination of arginineand glycine, which produce guanidinoacetate.A methyl group from SAM is then transferred,resulting in the formation of creatine. Thebyproduct of this reaction, S-adenosyl-homocysteine, is subsequently hydrolyzed intohomocysteine and adenosine.

Epinephrine and MelatoninDerivatives of the aromatic amino ac-

ids L-tyrosine and L-tryptophan, epinephrineand melatonin require methylation for biosyn-thesis of their down-line metabolites.

The biosynthesis of catecholaminesbegins with the amino acid L-tyrosine and pro-ceeds through dopa and dopamine, resultingin the formation of norepinephrine, the neuro-transmitter substance found in the majority ofsympathetic nerve terminals, as well as in somesynapses of the central nervous system. In thechromaffin cells of the adrenal medulla, amethyl group is provided by SAM, resultingin the formation of epinephrine from norepi-nephrine. A number of metabolites are formedfrom degradation of both norepinephrine andepinephrine. Catecholamine degradation pro-ceeds independently, in addition to in conjunc-tion with monoamine oxidase, by catechol-O-methyltransferase. This enzyme catalyzes thetransfer of a methyl group donated by SAMand, depending on the substrate, results in theformation of homovanillic acid, nor-metanephrine, and metanephrine.

Formation of melatonin from L-tryp-tophan proceeds through 5-hydroxy-tryp-tophan, serotonin, and N-acetylserotonin.Melatonin is then formed in the pineal glandby the donation of a methyl group. 5-Methoxytryptamine, an alternate metabolite ofserotonin, also requires the addition of a me-thyl group.

Since elevated homocysteine results insub-optimal synthesis of SAM, some impacton aromatic amino acid derivatives will oc-cur. The exact nature of the impact on cat-echolamine metabolites is still unclear, due toSAM’s role in both synthesis and degradation.It appears likely the biochemical stagnation as-sociated with elevated levels of homocysteinewould negatively impact melatonin synthesis.

PhosphatidylcholineDietary choline is derived primarily

from phosphatidylcholine (PC), a componentof lecithin. After absorption by the intestinalmucosa, PC is metabolized to choline in theliver by the enzyme phospholipase D. Mostcholine is re-phosphorylated to PC; however,a small amount is carried to the brain via theblood stream, where it is converted to the neu-rotransmitter acetylcholine. If PC or cholineare lacking in the diet they can be synthesizedfrom phosphatidylserine and phosphatidyl-ethanolamine. Synthesis of PC is dependenton the availability of SAM as a methyl donor,since synthesis involves the transfer of methylgroups from three SAM molecules to phos-phatidylethanolamine in order to generate onemolecule of PC (see Figure 4).

TaurineTaurine is a unique amino acid because

it carries a sulfonic acid group (-SO3H) instead

of a carboxyl group (-CO2H). Taurine is

biosynthesized from methionine or fromcysteine via the trans-sulfuration pathway (seeFigure 1). As discussed previously,homocysteine can be re-methylated to form

Hom

ocysteine



methionine; however, it can also be degradedto form cysteine. Once cysteine is generated itcan be directed into several different pathways,including synthesis of glutathione, acetyl-CoA, 3'-phosphate 5'-phosphosulfate (PAPS),and taurine. Degradation involves a two-stepprocess, resulting in formation of cystathionineand its subsequent cleavage to cysteine. Bothof the enzymes involved require P5P as acofactor, and the committed first step in thedegradation of homocysteine, utilizingcystathionine synthase, also requires serine. Inhumans, defects in both of these enzymaticreactions occur.

Homocysteine and Phase IIDetoxification Reactions

Because homocysteine is a critical in-termediate in both methyl and sulfur group me-tabolism, elevated levels could indicate nutri-ent deficiencies which might compromisefunction in virtually all phase II detoxificationreactions.

Amino acid conjugation reactions re-quire either glycine, glutamine, or taurine.Glycine functions in the conjugation of aro-matic acids (e.g., benzoic acid to hippuricacid). Elevated levels of homocysteine mightindicate reduced nutritional levels of betaineand subsequently its downline metabolite gly-cine. Taurine functions in acylations (e.g., bileconjugation). As discussed, optimal taurinesynthesis requires proper movement of ho-mocysteine into its degradation pathway. Thereare no known interactions between glutamineand homocysteine.

Sulfur conjugation requires N-acetylcysteine (NAC), glutathione (GSH),PAPS, or methionine/cysteine. NAC is usedfor mercapturic acid synthesis and is involvedin detoxification of a wide variety ofcompounds including aromatic hydrocarbons,some phenols, halides, esters, epoxides, andcaffeine. GSH is involved in dismutationreactions of organic nitrates (e.g.,

nitroglycerin). PAPS is utilized in sulfate estersynthesis, mostly with phenols, and somealiphatic alcohols (e.g., ethanol), and aromaticamines. Methionine and cysteine are used incyanide-thiocyanate detoxification. A portionof the inorganic sulfur needed for the formationof all these compounds passes through thehomocysteine cycle.

Alkylation reactions require SAM,methylcobalamin, or 5-methylTHF. Thesecompounds provide methyl groups to detoxifycompounds containing OH, SH, or NH

2groups. Examples of these reactions includenorepinephrine to epinephrine, epinephrine tometanephrine, guanidoacetic acid to creatine,and N-acetylserotonin to melatonin.

Other phase II detoxification reactionswhich might be impacted by elevated ho-mocysteine as a biological marker of reducednutrient formation include acetylation byacetylcoenzyme A, which requires cysteine asa source of its cysteamine component; and theuse of carnitine for the conversion of valproicacid to valpropylcarnitine

Homocysteine and Heart DiseaseA significant component in the patho-

genesis, prevention, and treatment of heart dis-ease involves the amino acid homocysteine.Increased blood levels of homocysteine arecorrelated with significantly increased risk ofcoronary artery disease (CAD),19-22 myocardialinfarction,23, 24 peripheral occlusive disease,25-

28 cerebral occlusive disease,25, 28 and retinalvascular occlusion.29

For over 25 years researchers haveknown inborn errors of homocysteine metabo-lism result in high levels of homocysteine inthe blood and severe atherosclerotic disease.We now know, even within the range which isconsidered normal (4-16 mumol/L), there is agraded increase in risk for CAD. In a study of304 patients with CAD vs. controls, Robinsonet al found the odds ratio for CAD increasedas plasma homocysteine increased, even within



the normal range. A 5 µmol/L increase inplasma homocysteine was correlated with anincrease in the odds ratio of 2.4 (p<.001), withno “threshold effect.”22

Data gathered by Boers30 from a num-ber of studies indicated that, after a methio-nine load test, mild hyperhomocysteinemiaoccured in 21%, 24%, and 32% of patientswith CAD, cerebrovascular disease, and peri-pheral vascular disease, respectively. Selhubet al found the incidence of hyper-homocysteinemia (>14 mumol/L by their defi-nition), in a group of 1160 elderly individuals(ages 67-96) in the Framingham Heart Study,to be 29.3%. The study also indicated plasmahomocysteine levels increase with age.25

Homocysteine facilitates the genera-tion of hydrogen peroxide.31 By creating oxi-dative damage to LDL cholesterol and endo-thelial cell membranes, hydrogen peroxidecan then catalyze injury to vascularendothelium.31, 32

Nitric oxide and other oxides ofnitrogen released by endothelial cells (alsoknown as endothelium-derived relaxing factor,or EDRF) protect endothelial cells fromdamage by reacting with homocysteine,forming S-nitrosohomocysteine, whichinhibits hydrogen peroxide formation.However, as homocysteine levels increase, thisprotective mechanism can become overloaded,allowing damage to endothelial cells tooccur.32-34 Because of the role of sulfatecompounds in the formation of amino sugarsneeded to form the basement membrane ofblood vessels, high levels of homocysteine arelikely to contribute to the formation of bloodvessels which are more susceptible to oxidativestress.34 The end result of the combination ofoxidative damage and endothelial collageninstability is the formation of atheroscleroticplaques.

Re-methylation of homocysteine andthe subsequent formation of SAM is criticalfor biosynthesis of L-carnitine, CoQ10, and

creatine. Similarly, the trans-sulfuration path-way must be functioning properly for optimalbiosynthesis of cysteine, GSH, pantethine, andtaurine. All of these nutrients are used clini-cally to either reduce oxidative stress, improverisk factor markers, or treat heart disease.

Decreased plasma folate levels are cor-related with increased levels of homocysteine,and a subsequent increased incidence of CAD.In a 15-year Canadian study of CAD mortal-ity in 5056 men and women 35-79 years ofage, lower serum folate levels were correlatedwith a significantly increased risk of fatalCAD.35 In a cohort from the Framingham HeartStudy, concentrations of folate and P5P wereinversely correlated with homocysteine levelsand the risk of extracranial carotid-arterystenosis.25 Low P5P and low vitamin B12 havealso been linked with hyperhomocysteinemiaand a significantly increased risk of CAD.22

If a dietary deficiency or an increaseddemand, resulting from genetic biochemicalindividuality, exists for 5-methylTHF,methylcobalamin, P5P, or betaine, treatmentwith these micro-nutrients should reducehomocysteine levels. Several studies utilizingfolic acid, B6, B12, and betaine either aloneor in combination have demonstrated theability of these nutrients to normalizehomocysteine levels.15, 26, 28, 36, 37 In a recentplacebo-controlled clinical study of 100 menwith hyperhomocysteinemia, oral therapy with650 mcg folic acid, 400 mcg vitamin B12, 10mg vitamin B6, or a combination of the threenutrients was given daily for six weeks. Plasmahomocysteine was reduced 41.7% (p<0.001)during folate therapy and 14.8% (p<0.01)during B12 therapy, while 10 mg B6 did notreduce plasma homocysteine significantly. Thecombination worked synergistically to reducehomocysteine levels 49.8%.38 In 68 patientswith recent myocardial infarction, 18% hadincreased plasma homocysteine. Oralfolate therapy (2.5 mg) reduced thishyperhomocysteinemia in 94% of treatedpatients (mean decrease 27%).23

Hom

ocysteine



A deficiency of the P5P dependent en-zyme cystathione synthase is the most com-mon genetic abnormality affecting the trans-sulfuration pathway of homocysteine break-down. Fortunately, B6 supplementation stimu-lates this enzyme and, in combination withbetaine, corrects the hyperhomocysteinemia inthese individuals.15, 36

Homocysteine and PeripheralVascular Disease

Elevated homocysteine levels havebeen established as an independent risk factorfor intermittent claudication (IC) and deep veinthrombosis. Elevated homocysteine levels cor-responded with an increased incidence of in-termittent claudication and decreased serumfolate levels in a study of 78 patients with IC.39

A four-fold increase in risk of peripheral vas-cular disease was noted in individuals withhyperhomocysteinemia compared to peoplewith normal homocysteine levels.40 A groupof researchers in the Netherlands found highhomocysteine levels to be a significant riskfactor for deep-vein thrombosis, with a stron-ger relationship among women than men.41

An increased risk of peripheral vascu-lar occlusion has been noted in women takingoral contraceptives, which might be linked tothe significantly increased homocysteine lev-els in women so affected. Oral contraceptivescan cause declines or deficiencies in vitaminsB6, B12, and folate, nutrients integral to theprocessing of homocysteine. Laboratory as-sessment of plasma homocysteine levels mightbe helpful to detect women who are predis-posed to peripheral vascular occlusion whileon oral contraceptives. 42

In a group of 48 patients with periph-eral atherosclerotic vascular disease, 50% hadabnormally high fasting plasma homocysteinelevels, while 100% had abnormal plasma ho-mocysteine after a methionine load. Treatmentwith 5 mg folic acid and 250 mg pyridoxinefor 12 weeks normalized 95% of the fasting

levels and 100% of post-load homocysteinelevels.26

Homocysteine and StrokeStroke patients have significantly el-

evated homocysteine levels compared to age-matched controls,43 with a linear relationshipexisting between risk of stroke and homocys-teine levels.44 Decreased blood folate concen-trations in stroke patients might be a possiblecause of the observed hyperhomo-cysteinemia.45

Homocysteine and PregnancyBiochemical enzyme defects and nu-

tritional deficiencies are receiving increasingattention for their role in causing neural tubedefects (NTD) as well as other negative preg-nancy outcomes, including spontaneous abor-tion, placental abruption (infarct), pre-termdelivery, and low infant birth weight. Recentevidence has suggested derangement of me-thionine-homocysteine metabolism could bethe underlying mechanism of pathogenesis ofneural tube defects and might be the mecha-nism of prevention observed with folic acidsupplementation.46, 47 A low dietary intake offolic acid increases the risk for delivery of achild with an NTD, and periconceptional folicacid supplementation reduces the NTD occur-rence.48-54 Supplemental folic acid intake alsoresults in increased infant birth weight andimproved Apgar scores, along with a concomi-tant decreased incidence of fetal growth retar-dation and maternal infections.55-58 A derange-ment in methionine-homocysteine metabolismhas also been correlated with recurrent mis-carriage and placental infarcts (abruption).59

The amino acid homocysteine, whenelevated, might be a teratogenic agent contrib-uting to congenital defects of the heart andneural tube. Evidence from experimental ani-mals lends support to this belief. When avianembryos were fed homocysteine to raise se-rum homocysteine to over 150 nmol/ml,



dysmorphogenesis of the heart and neural tube,as well as of the ventral wall, were observed.60

Because homocysteine metabolism,through the re-methylation and trans-sulfuration pathways, affects several biochemi-cal pathways involving the production of nu-trients which are essential to the optimal func-tioning of the cardiovascular, skeletal, andnervous systems, it is not surprising these othernutrients have been linked to complications ofpregnancy in animal models and humans. Lowplasma vitamin B12 levels have been shownto be an independent risk factor for NTD.61,62

Methionine supplementation has been shownto reduce the incidence of NTD by 41% in ananimal model.63,64 This evidence indicates thata disturbance in the re-methylation pathway,with a subsequent decrease in SAM, might bea contributing factor to these complications ofpregnancy. Phosphatidylcholine, due to its roleas a precursor to acetylcholine and choline, isacknowledged as a critical nutrient for brainand nerve development and function.65-67 Sincethe metabolic pathways of choline (via be-taine), methionine, methylcobalamin, and 5-methylTHF are interrelated, intersecting at theregeneration of methionine from homocys-teine, a disturbance in the metabolism of ei-ther of these two methyl-donor pathways, dueto limited availability of key nutrients or de-creased enzyme activity, will have a directimpact on the body’s ability to optimize SAMlevels.

Evidence suggests women with a his-tory of NTD-affected pregnancies have alteredfolic acid metabolism.68-71 Patients with a se-vere congenital deficiency of the enzyme 5,10-methylenetetrahydrofolate reductase(MTHFR), which is needed for the formationof 5-methylTHF, have reduced levels of bothmethionine and SAM in the cerebrospinalfluid, and show demyelination in the brain anddegeneration of the spinal cord.2, 72 Because ofits direct impact in the activation of folic acidto its methyl derivative, a milder version of

this enzyme defect is also strongly suspectedto increase incidence of NTD.73

High vitamin A intake during the firsttwo months of pregnancy is associated with aseveral-fold higher incidence of birth de-fects.74,75 Although the mechanism of actionremains to be elicited, in an animal model theactivity of hepatic MTHFR is suppressed withhigh vitamin A levels,76 suggesting its terato-genic effect during early pregnancy might beassociated with subsequent derangement in there-methylation of homocysteine.

Since a significant correlation has beenfound between higher homocysteine levels inwomen experiencing placental abruption, in-farction, and spontaneous abortion than in con-trol women, and since homocysteine andCoQ10 synthesis are both dependent on themethionine-SAM-homocysteine pathway, it ispossible low CoQ10 and elevated homocys-teine, independently found in complicatedpregnancy, might also in fact be found to berelated conditions.77, 78

Homocysteine and the NervousSystem

In addition to the known impact ofhomocysteine on the cardiovascular systemand micro-nutrient biochemical pathways,numerous diseases of the nervous system arecorrelated with high homocysteine levels andalterations in B12, folate, or B6 metabolism,including depression, schizophrenia, multiplesclerosis, Parkinson’s disease, Alzheimer’sdisease, and cognitive decline in the elderly.

Methylation reactions via SAM,including methylation of DNA and myelin, arevitally important in the CNS. The neurologiccomplications of vitamin B12 deficiency arethought to be due to a reduction of activity ofthe B12-dependent enzyme methioninesynthase, and the subsequent reduction ofSAM production. The CNS lacks the alternatebetaine pathway of homocysteineremethylation; therefore, if methionine

Hom

ocysteine



synthase is inactivated, the CNS has a greatlyreduced methylation capacity.79 Other causesof reduced methionine synthase activityinclude folic acid deficiency and nitrous oxideanesthesia exposure.80

Homocysteine has also been found tobe a neurotoxin, especially in conditions inwhich glycine levels are elevated, includinghead trauma, stroke,81 and B12 deficiency. Ho-mocysteine interacts with the N-methyl-D-as-partate receptor, causing excessive calciuminflux and free radical production, resultingin neurotoxicity.81 The neurotoxic effects ofhomocysteine and/or reduced methylation re-actions in the CNS contribute to the mentalsymptomatology seen in B12 and folate defi-ciency. Increased homocysteine levels can alsobe seen in schizophrenics.82

Significant deficiencies in B12 andfolate are common in the elderly population,and can contribute to a decline in cognitivefunction.83-85 An investigation of cognitive abil-ity in older men (ages 54-81) found poorerspatial copying skills in those individuals withhigher homocysteine levels. Better memoryperformance was correlated with higher vita-min B6 levels.86

B12 deficiency and increasing severityof cognitive impairment has been seen inAlzheimer’s disease (AD) patients comparedto controls and patients with other dementias.87

In a study of 52 AD patients, 50 hospitalizednon-demented controls, and 49 elderly subjectsliving at home, patients with AD were foundto have the highest homocysteine levels andthe highest methylmalonic acid (an indicatorof B12 deficiency) levels.88 In a study of 741psychogeriatric patients, high plasmahomocysteine levels were found in dementedand non-demented patients; however, onlydemented patients also had lower blood folateconcentrations compared to controls. Patientswith concomitant vascular disease hadsignificantly higher plasma homocysteine thanthose without diagnosed vascular disease.

Significantly higher homocysteine levels,compared to controls, have also been found inParkinson’s patients.89

Homocysteine’s effects on neurotrans-mitter metabolism, along with its potential re-duction of methylation reactions, could be acontributing factor to the etiology of depres-sion. Folate and B12 deficiency can cause neu-ropsychiatric symptoms, including dementiaand depression. Although no studies have beenperformed to date investigating depression,folate and B12 deficiency, and homocysteinelevels, the informatiuon regarding these defi-ciencies and methionine synthase inhibitionsuggests this connection will be revealed inthe future. SAM is used therapeutically as anantidepressant in Europe,90, 91 and was the thirdmost popular antidepressant treatment in Italyin 1995.91 As yet, SAM is not available as asupplement in the United States.

Methylation of myelin basic protein isvital to maintenance of the myelin sheath. Theworst-case scenario of folate and B12 defi-ciency includes demyelination of the posteriorand lateral columns of the spinal cord, a dis-ease process called subacute combined degen-eration of the spinal cord (SCD).79 SCD canalso be precipitated by nitrous oxide anesthe-sia, which causes an irreversible oxidation ofthe cobalt moiety of the B12 molecule and thesubsequent inhibition of methionine synthaseactivity, a decrease in homocysteine re-methyl-ation, and decreased SAM production.80 Thishas been treated using supplemental methio-nine, which further supports the theory of anitrous oxide-induced biochemical block atmethionine synthase.92 Particularly at risk forthis condition are B12-deficient individualswho visit their dentist and receive nitrous ox-ide.80, 93

Abnormal methylcobalamin metabo-lism is a proposed mechanism for thepathophysiology of the demyelinating diseasemultiple sclerosis (MS). Deficiency of vitaminB12 has been linked to some MS cases, and itis suggested dietary deficiency, or more likely,



a defect in R-protein-mediated absorption ormethylation of B12, might be a significantcontributor to MS pathogenesis.94

Patients with congenital MTHFR de-ficiency, which is needed for the formation of5-methylTHF, have reduced levels of both me-thionine and SAM in the cerebrospinal fluid(CSF) and show demyelination in the brain anddegeneration of the spinal cord. Methionine iseffective in the treatment of some of these pa-tients; however, betaine was shown to restoreCSF SAM levels to normal and to prevent theprogress of neurological symptoms in all pa-tients in whom it was tried.95

Homocysteine and Diabetes MellitusHomocysteine levels appear to be

lower in individuals with type I diabetes mel-litus. Forty-one type I diabetic subjects (age34.8 ± 12 yr, duration of illness; 10.7 ± 11.1yr) were compared to 40 age-matched controlsubjects (age 34.2 ±9.1 yr). Following an over-night fast, homocysteine was significantlylower (p = 0.0001) in the diabetic group (6.8± 2.2) than in controls (9.5 ± 2.9). This differ-ence was apparent in male and female sub-groups.96 However, increased levels of ho-mocysteine have been reported in type I dia-betics with proliferative retinopathy97 andnephropathy.97, 98

Evidence to date suggests metabolismof homocysteine is also impaired in patientswith non-insulin-dependent diabetes mellitus(NIDDM). Following a methionine load,hyperhomocysteinemia occurred withsignificantly greater frequency in patients withNIDDM (39%) as compared with age-matchedcontrols (7%). The area under the curve over24 hours, reflecting the total period of exposureto increased homocysteine, was also elevatedwith greater frequency in patients withNIDDM and macrovascular disease (33%) ascompared with controls (0%). The authorsconcluded hyperhomocysteinemia isassociated with macrovascular disease in a

significant proportion of patients withNIDDM.99 Araki et al also reported increasedhomocysteine levels correlate with theoccurrence of macroangiopathy in patientswith NIDDM. Intramuscular injection of 1000micrograms methylcobalamin daily for threeweeks reduced the elevated plasma levels ofhomocysteine in these individuals.100

Elevated homocysteine levels appearto be a risk factor for diabetic retinopathy. Thismight be due to a point mutation on the genefor the enzyme MTHFR,101, 102 as a significantlyhigher percentage of diabetics with retinopa-thy exhibit this mutation.102 Elevated homocys-teine levels cause cell injury to the small ves-sels, which might contribute to develop-ment of retinopathy and cardiovascularmacroangiopathy.101

Homocysteine and RheumatoidArthritis

Elevated total homocysteine levelshave been reported in patients with rheumatoidarthritis (RA). Twenty-eight patients with RAand 20 healthy age-matched control subjectswere assessed for homocysteine levels, whilefasting and in response to a methioninechallenge. Fasting levels were 33% higher inRA patients than in controls. Four hoursfollowing the methionine challenge, theincrease in plasma homocysteineconcentration was also higher in patients withrheumatoid arthritis.103 Another study foundstatistically significant increases inhomocysteine in RA patients (p = 0.003), with20% of the patients having homocysteinelevels above the reference range.104 Amechanism for this increased homocysteine inRA patients has not been elucidated.Penicillamine, a common sulfhydryl-containing arthritis treatment, has been foundto lower elevated homocysteine levels invivo.105 Further investigation into both theprevalence of hyperhomocysteinemia and themechanism of action impacting rheumatoidarthritis is needed.

Hom

ocysteine



Homocysteine and Kidney FailureBecause homocysteine is cleared by

the kidneys, chronic renal failure, as well asabsolute or relative deficiencies of 5-methylTHF, methylcobalamin, P5P, or betaine,results in increased homocysteine levels. In176 patients with end-stage renal disease onperitoneal- or hemodialysis, homocysteineconcentrations averaged 26.6 ± 1.5 µmol/L inpatients with renal failure as compared to 10.1± 1.7 µmol/L in normals. Abnormal valuesexceeded the 95th percentile for normal con-trols in 149 of the patients with renal failure.106

Data also indicates plasma homocysteine val-ues represent an independent risk factor forvascular events in patients on peritoneal- andhemodialysis. Patients with a homocysteineconcentration in the upper two quintiles (> 27.8µmol/L) had an independent odds ratio of 2.9(CI, 1.4 to 5.8; P = .007) of vascular compli-cations. B vitamin levels were also lower inpatients with vascular complications than inthose without.107

Homocysteine and EthanolIngestion

Chronic alcoholism is known to inter-fere with one-carbon metabolism. Because ofthis, it is not surprising to find mean serumhomocysteine concentrations twice as high inchronic alcoholics as compared to nondrink-ers (p < 0.001). Beer consumers have lowerconcentrations of homocysteine than drinkersof wine or spirits (p = 0.05). In chronic alco-holics, serum P5P and red blood cell folateconcentrations have been shown to be signifi-cantly lower than in control subjects.10

Hultberg et al reported a significantly higherconcentration of plasma homocysteine, com-pared with controls, in 42 active alcoholicshospitalized for detoxification. In anothergroup of 16 alcoholics, abstaining from etha-nol ingestion, plasma homocysteine did notdeviate from levels found in controls.11

Feeding ethanol to rats producesprompt inhibition of methionine synthase aswell as a subsequent increase in activity ofbetaine homocysteine methyltransferase. De-spite the inhibition of methionine synthase, theenhanced betaine homocysteine methyltrans-ferase pathway utilizes hepatic betaine poolsto maintain levels of SAM.108 Results indicateethanol feeding produces a significant SAMloss in the first week, with a return to normalSAM levels the second week. Betaine feedingenhances hepatic betaine pools in control aswell as ethanol-fed animals, attenuates theearly SAM loss in ethanol-fed animals, pro-duces an early increase in betaine homocys-teine methyltransferase activity, and generatesincreased SAM levels in both control and etha-nol-fed groups.109 Minimal supplemental di-etary betaine at the 0.5% level generates SAMtwofold in control animals and fivefold in etha-nol-fed rats. Concomitant with betaine-gener-ated SAM, ethanol-induced hepatic fatty in-filtration was ameliorated.121 Betaine supple-mentation also reduces the accumulation ofhepatic triglycerides produced after ethanolingestion.109

Homocysteine and GoutAlthough homocysteine levels have

been positively correlated with increased uricacid levels,2, 110, 111 no studies exist to date whichhave investigated homocysteine levels in goutpatients. It is possible increased uric acid levelsin gout are due to decreased SAM productionbecause of the reduction in homocysteinerecycling. The excess adenosine, which wouldhave reacted with methionine to form SAM,is degraded to form uric acid as its end product.

Niacin is contraindicated in gout, as itcompetes with uric acid for excretion.112 Inanimal studies, increased levels ofS-adenosylhomocysteine (SAH), and thushomocysteine, cause significant reductions inSAM-dependent methylation reactions.12

Therefore, since degradation of the niacin-containing coenzyme nicotinamide adenine



dinucleotide (NAD) is dependent onmethylation by SAM, and SAM activity isseverely reduced in hyperhomocysteinemia,niacin levels might be higher in these people,resulting in less uric acid excretion, higher uricacid levels, and increased gout symptoms insusceptible individuals.

Additionally, one study indicates nia-cin supplementation increases homocysteinelevels. In the Arterial Disease Multiple Inter-vention Trial,113 niacin supplementation of lessthan one gram per day increased serum ho-mocysteine levels by 55% over an 18-weekperiod. A similar outcome was noted in ananimal study, which took the investigation onestep further by adding vitamin B6 to the regi-men. B6-supplemented animals showed a re-versal of the niacin-induced hyperhomo-cysteinemia compared to non-B6-supple-mented animals.114 Extrapolating from this re-search, it seems prudent to supplement vita-min B6 if high-dose niacin is to be used forhyperlipidemia treatment. And, since niacinneeds to be methylated for its degradation,providing the methyl-donating nutrients be-taine, B12, and folate also makes sense.

Homocysteine and OsteoporosisHomocystinuria due to cystathionine

synthase deficiency is an autosomal recessiveerror of sulfur amino acid metabolismcharacterized clinically by lens dislocation,mental retardation, skeletal abnormalities, andthromboembolic phenomena.115 Individualswith this enzyme deficiency have increasedconcentrations of homocysteine and decreasedconcentrations of cysteine and its disulfideform, cystine. In children with homocystinuria,osteoporosis is a common presentingsymptom.116 Because of the role of sulfurcompounds in formation of sulfated aminosugars, disturbed cross-linking of collagen hasbeen proposed as a possible mechanism ofaction. Lubec et al examined 10 patients withhomocystinuria. They found synthesis of

collagen was normal; however, they reporteda significant reduction of cross-links in thegroup with homocystinuria.117

Because of the correlation betweenhomocystinuria and osteoporosis in childrenwith this amino acidopathy, and because of theincrease in homocysteine concentrations inpostmenopausal woman, several authors haveimplied elevated homocysteine levels contrib-ute to postmenopausal osteoporosis. To date,no evidence is available which demonstrateshomocysteine levels are higher in postmeno-pausal women with osteoporosis than in age-matched controls.

Diagnostic ConsiderationsMany of the studies referenced herein

have used 12-16 µMol/L as the upper limit ofthe normal range for homocysteine levels. Weprobably will see this level drop, as we didwith cholesterol testing, since, even within the“normal” range, the relative risk ofatherosclerotic cardiovascular disease, andmost likely other disease processes, increasesas homocysteine levels increase. A number ofclinical laboratories currently perform plasmahomocysteine determinations, either alone orcombined with a cardiovascular panel.Additionally, either elevated creatinine or uricacid levels on a blood chemistry panel mightwarrant further investigation for elevatedhomocysteine levels.

A one-time, fasting determination ofplasma homocysteine will show hyper-homocysteinemia in clear-cut cases. Othercases will not be uncovered unless the path-ways of homocysteine metabolism arestressed, as with the methionine loading test.An oral dosage of 100mg/kg methionine isgiven, followed by a plasma homocysteinedetermination six hours later. The methionineloading test might be a more reliable assay, asit can reveal those individuals who would nothave hyperhomocysteinemia on a fastingsample.

Hom

ocysteine



ConclusionElevated homocysteine levels have

been confirmed as an independent risk factorfor atherosclerotic cardiovascular disease, andare implicated in a number of other vascular,neuropsychiatric, renal, skeletal, perinatal, andendocrine diseases. Supplementation with thenutrient cofactors required for optimal func-tioning of the methionine/homocysteine meta-bolic pathways significantly impacts homocys-teine levels, and offers a new integrated possi-bility for primary prevention. Betaine, vitaminB12, folic acid, and vitamin B6 assist in opti-mizing methyl and sulfur group metabolismand their use might play a significant role inthe prevention and treatment of a wide arrayof clinical conditions. With the current empha-sis on homocysteine research (over 1000 ar-ticles on homocysteine published in the sci-entific literature in the past five years) it is verylikely that these disease connections will befurther confirmed and others will be revealedin the months and years to come.

References1. Tucker KL, Selhub J, Wilson PW, Rosenberg

IH. Dietary intake pattern relates to plasmafolate and homocysteine concentrations in theFramingham Heart Study. J Nutr1996;126:3025-3031.

2. Lussier-Cacan S, Xhignesse M, Piolot A, et al.Plasma total homocysteine in healthy subjects:sex-specific relation with biological traits. AmJ Clin Nutr 1996;64:587-593.

3. van der Mooren MJ, Wouters MG, Blom HJ, etal. Hormone replacement therapy may reducehigh serum homocysteine in postmenopausalwomen. Eur J Clin Invest 1994;24:733-736.

4. Wouters MG, Moorrees MT, Van der MoorenMJ, et al. Plasma homocysteine and meno-pausal status. Eur J Clin Invest 1995;25:801-805.

5. Brattstrom L, Lindgren A, Israelsson B, et al.Homocysteine and cysteine: determinants ofplasma levels in middle-aged and elderlysubjects. J Intern Med 1994;236:633-641.

6. Nygard O, Vollset SE, Refsum H, et al. Totalplasma homocysteine and cardiovascular riskprofile—the Hordaland homocysteine study.JAMA 1995;274:1526-1533.

7. Anker G, Lonning PE, Ueland PM, et al.Plasma levels of the atherogenic amino acidhomocysteine in post-menopausal women withbreast cancer treated with tamoxifen. Int JCancer 1995;60:365-368.

8. Vermaak WJ, Ubbink JB, Delport R, et al.Ethnic immunity to coronary heart disease?Atherosclerosis 1991;89:155-162.

9. Nygard O, Refsum H, Ueland PM, et al.Coffee consumption and plasma total ho-mocysteine: The Hordaland HomocysteineStudy. Am J Clin Nutr 1997;65:136-143.

10. Cravo ML, Gloria LM, Selhub J, et al.Hyperhomocysteinemia in chronic alcoholism:correlation with folate, vitamin B-12, andvitamin B-6 status. Am J Clin Nutr1996;63:220-224.

11. Hultberg B, Berglund M, Andersson A, FrankA. Elevated plasma homocysteine in alcohol-ics. Alcohol Clin Exp Res 1993;17:687-689.

12. Duerre JA, Briske-Anderson M. Effect ofadenosine metabolites on methyltransferasereactions in isolated rat livers. BiochimBiophys Acta 1981;678:275-282.

13. Wiklund O, Fager G, Andersson A, et al. N-acetylcysteine treatment lowers plasmahomocysteine but not serum lipoprotein(a)levels. Atherosclerosis 1996;119:99-106.

14. Spector R. Cerebrospinal fluid folate and theblood-brain barrier. In: Botez MI, ReynoldsEH. Folic acid in neurology, psychiatry, andinternal medicine. New York: Raven Press;1979:187.

15. Wilcken DE, Dudman NP, Tyrrell PA.Homocystinuria due to cystathionine beta-synthase deficiency—the effects of betainetreatment in pyridoxine-responsive patients.Metabolism 1985;12:1115-1121.

16. Dudman NP, Guo XW, Gordon RB, et al.Human homocysteine catabolism: three majorpathways and their relevance to developmentof arterial occlusive disease. J Nutr1996;126:1295S-1300S.

17. Daily JW 3rd, Sachan D. Choline supplemen-tation alters carnitine homeostasis in humansand guinea pigs. J Nutr 1995;125:1938-1944.



18. Dodson W, Sachan D. Choline supplementa-tion reduces urinary carnitine excretion inhumans. Am J Clin Nutr 1996;63:904-910.

19. Hopkins P, Wu L, Wu J, et al. Higher plasmahomocyst(e)ine and increased susceptibility toadverse effects of low folate in early familialcoronary artery disease. Arterioscler ThrombVasc Biol 1995;15:1314-1320.

20. Loehrer F, Angst C, Haefeli W, et al. Lowwhole-blood S-adenosylmethionine andcorrelation between 5-methyltetrahydrofolateand homocysteine in coronary artery disease.Arterioscler Thromb Vasc Biol 1996;16:227-233.

21. Boushey C, Beresford S, Omenn G, MotulskyA. A quantitative assessment of plasmahomocysteine as a risk factor for vasculardisease. Probable benefits of increasing folicacid intakes. JAMA 1995;274:1049-1057.

22. Robinson K, Mayer E, Miller D, et al.Hyperhomocysteinemia and low pyridoxalphosphate. Common and independent revers-ible risk factors for coronary artery disease.Circulation 1995;92:2825-2830.

23. Landgren F, Israelsson B, Lindgren A, et al.Plasma homocysteine in acute myocardialinfarction: homocysteine-lowering effect offolic acid. J Int Med 1995;237:381-388.

24. Chasan-Taber L, Selhub J, Rosenberg I, et al.A prospective study of folate and vitamin B6and risk of myocardial infarction in U.S.physicians. J Am Coll Nutr 1996;15:136-143.

25. Selhub J, Jacques P, Bostom A, et al. Associa-tion between plasma homocysteine concentra-tions and extracranial carotid-artery stenosis. NEngl J Med 1995;332:286-291.

26. van den Berg M, Boers G, Franken D, et al.Hyperhomocysteinaemia and endothelialdysfunction in young patients with peripheralarterial occlusive disease. Eur J Clin Invest1995;25:176-181.

27. van den Berg M, Stehouwer C, Bierdrager E,Rauwerda J. Plasma homocysteine andseverity of atherosclerosis in young patientswith lower-limb atherosclerotic disease.Arterioscler Thromb Vasc Biol 1996;16:165-171.

28. Franken D, Boers G, Blom H, et al. Treatmentof mild hyperhomocysteinaemia in vasculardisease patients. Arterioscler Thromb Vasc Biol1994;14:465-470.

29. Wenzler E, Rademakers A, Boers G, et al.Hyperhomocysteinemia in retinal artery andretinal vein occlusion. Am J Ophthalmol1993;115:162-167.

30. Boers G. Hyperhomocysteinaemia: a newlyrecognized risk factor for vascular disease.Neth J Med 1994;45:34-41.

31. Starkebaum G, Harlan JM. Endothelial cellinjury due to copper-catalyzed hydrogenperoxide generation from homocysteine. J ClinInvest 1986;77:1370-1376.

32. Stamler J, Osborne J, Jaraki O, et al. Adversevascular effects of homocysteine are modu-lated by endothelium-derived relaxing factorand related oxides of nitrogen. J Clin Invest1993;91:308-318.

33. Stamler J, Loscalzo J. Endothelium-derivedrelaxing factor modulates the atherothrom-bogenic effects of homocysteine. J CardiovascPharmacol 1992;12:S202-S204.

34. Stamler J, Slivka A. Biological chemistry ofthiols in the vasculature-related disease. NutrRev 1996;54:1-30.

35. Morrison H, Schaubel D, Desmeules M, WigleD. Serum folate and risk of fatal coronaryheart disease. JAMA 1996;275:1893-1896.

36. Dudman N, Wilcken D, Wang J, et al. Disor-dered methionine/homocysteine metabolism inpremature vascular disease. Its occurence,cofactor therapy, and enzymology. ArteriosclerThromb 1993;13:1253-1260.

37. Wilcken DE, Wilcken B, Dudman NP, TyrrellPA. Homocystinuria—the effects of betaine inthe treatment of patients not responsive topyridoxine. N Engl J Med 1983;309:448-453.

38. Ubbink J, Vermaak W, van der Merwe, et al.Vitamin requirements for the treatment ofhyperhomocysteinemia in humans. J Nutr1994;124:1927-1933.

39. Molgaard J, Malinow MR, Lassvik C, et al.Hyperhomocyst(e)inaemia: an independentrisk factor for intermittent claudication. JIntern Med 1992;231:273-279.

40. Cheng SW, Ting AC, Wong J. Fasting totalplasma homocysteine and atheroscleroticperipheral vascular disease. Ann Vasc Surg1997;11:217-223.

41. den Heijer M, Koster T, Blom HJ, et al.Hyperhomocysteinemia as a risk factor fordeep-vein thrombosis. N Engl J Med1996;334:759-762.

Hom

ocysteine



42. Beaumont V, Malinow MR, Sexton G, et al.Hyperhomocyst(e)inemia, anti-estrogenantibodies and other risk factors for thrombosisin women on oral contraceptives. Atherosclero-sis 1992;94:147-152.

43. Brattstrom L, Lindgren A, Israelsson B, et al.Hyperhomocysteinaemia in stroke: prevalence,cause, and relationships to type of stroke andstroke risk factors. Eur J Clin Invest1992;22:214-221.

44. Perry IJ, Refsum H, Morris RW, et al. Prospec-tive study of serum total homocysteineconcentration and risk of stroke in middle-agedBritish men. Lancet 1995;346:1395-1398.

45. Hultberg B, Andersson A, Lindgren A.Marginal folate deficiency as a possible causeof hyperhomocystinaemia in stroke patients.Eur J Clin Chem Clin Biochem 1997;35:25-28.

46. Eskes TK. Possible basis for primary preven-tion of birth defects with folic acid. FetalDiagn Ther 1994;9:149-154.

47. Steegers-Theunissen R, Boers G, Trijbels FJ,Eskes TK. Neural-tube defects and derange-ment of homocysteine metabolism. N Engl JMed 1991;324:199-200 [letter].

48. MRC Vitamin Study Research Group. Preven-tion of neural tube defects: results of theMedical Research Council Vitamin Study.Lancet 1991;338:131-137.

49. Vergel RG, Sanchez LR, Heredero BL, et al.Primary prevention of neural tube defects withfolic acid supplementation: Cuban experience.Prenat Diag 1990;10:149-152.

50. Milunsky A, Jick H, Jick SS, et al. Multivita-min/folic acid supplementation in earlypregnancy reduces the prevalence of neuraltube defects. JAMA 1989;262:2847-2852.

51. Czeizel AE, Dudas I. Prevention of the firstoccurrence of neural-tube defects bypericonceptional vitamin supplementation. NEngl J Med 1992;327:1832-1835.

52. Bower C, Stanley FJ. Dietary folate as a riskfactor for neural tube defects: evidence from acase-controlled study in Western Australia.Med J Aust 1989;150:613-619.

53. Werler MM, Shapiro S, Mitchell AA.Periconceptional folic acid exposure and riskof occurrent neural tube defects. JAMA1993;269:1257-1261.

54. Shaw GM, Schaffer D, Velie EM, et al.Periconceptional vitamin use, dietary folate,and the occurrence of neural tube defects.Epidemiology 1995;6:219-226.

55. Tamura T, Goldenberg R, Freeberg L, et al.Maternal serum folate and zinc concentrationsand their relationships to pregnancy outcome.Am J Clin Nutr 1992;56:365-370.

56. Scholl TO, Hediger ML, Schall JI, et al.Dietary and serum folate: their influence onthe outcome of pregnancy. Am J Clin Nutr1996;63:520-525.

57. Frelut ML, deCoucy GP, Christides JP, et al.Relationship between maternal folate statusand foetal hypotrophy in a population with agood socio-economical level. Int J VitaminNutr Res 1995;65:267-271.

58. Goldenberg RL, Tamura T, Cliver SP, et al.Serum folate and fetal growth retardation: amatter of compliance? Obstet Gynecol1992;79:719-722.

59. Goddijn-Wessel, Toos AW, et al.Hyperhomocysteinemia: A risk factor forplacental abruption or infarction. Eur J ObstGyn Reprod Biol 1996;66:23-29.

60. Rosenquist TH, Ratashak SA, Selhub J.Homocysteine induces congenital defects ofthe heart and neural tube: effect of folic acid.Proc Natl Acad Sci 1996;93:15227-15232.

61. Kirby PN, Molloy AM, Daly LE, et al.Maternal plasma folate and vitamin B12 areindependent risk factors for neural tubedefects. Q J Med 1993;86:703-708.

62. Mills JL, Scott JM, Kirke PN, et al. Homocys-teine and neural tube defects. J Nutr1996;126:756S-760S.

63. Essien FB, Wannberg SL. Methionine but notfolinic acid or vitamin B-12 alters the fre-quency of neural tube defects in Axd mutantmice. J Nutr 1993;123:973-974.

64. Potier de Courcy G, Bujoli J. Effects of dietswith or without folic acid, with or withoutmethionine, on fetus development, folate storesand folic acid-dependent enzyme activities inthe rat. Biol Neonate 1981;39:132-140.

65. Zeisel SH. Choline and human nutrition. AnnuRev Nutr 1994;14:269-296.

66. Garner SC, Mar MH, Zeisel SH. Cholinedistribution and metabolism in pregnant ratsand fetuses are influenced by the cholinecontent of the maternal diet. J Nutr1995;125:2851-2858.

67. Meck WH, Smith RA, Williams CL. Pre- andpostnatal choline supplementation produceslong-term facilitation of spatial memory. DevPsychobiol 1988;21:339-353.



68. Wild J, Seller MJ, Schorah CJ, Smithells RW.Investigation of folate intake and metabolismin women who have had two pregnanciescomplicated by neural tube defects. Br JObstet Gynaecol 1994;101:197-202.

69. Wild J, Schorah CJ, Sheldon TA, SmithellsRW. Investigation of factors influencing folatestatus in women who have had a neural tubedefect-affected infant. Br J Obstet Gynaecol1993;100:546-549.

70. Yates JR, Ferguson-Smith MA, Shenkin A, etal. Is disordered folate metabolism the basisfor the genetic predisposition to neural tubedefects? Clin Genet 1987;31:279-287.

71. Lucock MD, Wild J, Schorah CJ, et al. Themethylfolate axis in neural tube defects: invitro characterisation and clinical investiga-tion. Biochem Med Metabol Biol 1994;52:101-114.

72. Kluijtmans LA, Van den Heuvel LP, Boers GH,et al. Molecular genetic analysis in mildhyperhomocysteinemia: a common mutation inthe methylenetetrahydrofolate reductase geneis a genetic risk factor in cardiovasculardisease. Am J Hum Genet 1996;58:35-41.

73. Whitehead AS, Gallagher P, Mills JL. Agenetic defect in 5,10 methylenetetra-hydrofolate reductase in neural tube defects.QJM 1995;88:763-766.

74. Kubler W. Nutritional deficiencies in preg-nancy. Bibl Nutr Dieta 1981;30:17-29.

75. Martinez-Frias ML, Salvador J. Epidemiologi-cal aspects of prenatal exposure to high dosesof vitamin A in Spain. Eur J Epidemiol1990;6:118-123.

76. Fell D, Steele RD. Modification of hepaticfolate metabolism in rats fed excess retinol.Life Sci 1986;38:1959-1965.

77. Noia G, Littarru GP, De Santis M, et al.Coenzyme Q10 in pregnancy. Fet Diag Ther1996;11:264-270.

78. Noia G, Lippa S, Di Maio A, et al. Bloodlevels of coenzyme Q10 in early phase ofnormal or complicated pregnancies. In: FolkersK, Yamamura Y. Biomedical and ClinicalAspects of Coenzyme Q. Amsterdam: Elsevier;1991: 209-213.

79. Weir DG, Scott JM. The biochemical basis ofthe neuropathy in cobalamin deficiency.Baillieres Clin Haematol 1995;8:479-497.

80. Flippo TS, Holder WD Jr. Neurologic degen-eration associated with nitrous oxide anesthe-sia in patients with vitamin B12 deficiency.Arch Surg 1993;128:1391-1395.

81. Lipton SA, Kim WK, Choi YB, et al. Neuro-toxicity associated with dual actions ofhomocysteine at the N-methyl-D-aspartatereceptor. Proc Natl Acad Sci 1997;94:5923-5928.

82. Regland B, Johansson BV, Grenfeldt B, et al.Homocysteinemia is a common feature ofschizophrenia. J Neural Transm Gen Sect1995;100:165-169.

83. Metz J, Bell AH, Flicker L, et al. The signifi-cance of subnormal serum vitamin B12concentration in older people: a case controlstudy. J Am Geriatr Soc 1996;44:1355-1361.

84. Quinn K, Basu TK. Folate and vitamin B12status of the elderly. Eur J Clin Nutr1996;50:340-342.

85. Fine EJ, Soria ED. Myths about vitamin B12deficiency. South Med J 1991;84:1475-1481.

86. Riggs KM, Spiro A 3rd, Tucker K, Rush D.Relations of vitamin B-12, vitamin B-6, folate,and homocysteine to cognitive performance inthe Normative Aging Study. Am J Clin Nutr1996;63:306-314.

87. Levitt AJ, Karlinsky H. Folate, vitamin B12and cognitive impairment in patients withAlzheimer’s disease. Acta Psychiatr Scand1992;86:301-305.

88. Joosten E, Lesaffre E, Riezler R, et al. Ismetabolic evidence for vitamin B-12 and folatedeficiency more frequent in elderly patientswith Alzheimer’s disease? J Gerontol A BiolSci Med Sci 1997;52:M76-M79.

89. Allain P, Le Bouil A, Cordillet E, et al. Sulfateand cysteine levels in the plasma of patientswith Parkinson’s disease. Neurotoxicology1995;16:527-529.

90. Reynolds EH, Carney MW, Toone BK.Methylation and mood. Lancet 1984;2:196-198.

91. Arpino C, Da Cas R, Donini G, et al. Use andmisuse of antidepressant drugs in a randomsample of the population of Rome, Italy. ActaPsychiatr Scand 1995;92:7-9

92. Stacy CB, Di Rocco A, Gould RJ. Methioninein the treatment of nitrous-oxide-inducedneuropathy and myeloneuropathy. J Neurol1992;239:401-403.

Hom

ocysteine



93. Schilling RF. Is nitrous oxide a dangerousanesthetic for vitamin B12-deficient subjects?JAMA 1986;255:1605-1606.

94. Reynolds EH, Bottiglieri T, Laundy M, et al.Vitamin B12 metabolism in multiple sclerosis.Arch Neurol 1992;49:649-652.

95. Hyland K, Smith I, Bottiglieri T, et al. Demy-elination and decreased S-adenosylmethioninein 5, 10-methylenetetradydrofolate reductasedeficiency. Neurology 1988;38:459-462.

96. Robillon JF, Canivet B, Candito M, et al. Type1 diabetes mellitus and homocyst(e)ine.Diabete Metab 1994;20:494-496.

97. Hultberg B, Agardh E, Andersson A, et al.Increased levels of plasma homocysteine areassociated with nephropathy, but not severeretinopathy in type 1 diabetes mellitus. Scand JClin Lab Invest 1991;51:277-282.

98. Agardh CD, Agardh E, Andersson A, HultbergB. Lack of association between plasmahomocysteine levels and microangiopathy intype 1 diabetes mellitus. Scand J Clin LabInvest 1994;54:637-641.

99. Munshi MN, Stone A, Fink L, Fonseca V.Hyperhomocysteinemia following a methion-ine load in patients with non-insulin-dependentdiabetes mellitus and macrovascular disease.Metabolism 1996;45:133-135.

100. Araki A, Sako Y, Ito H. Plasma homocysteineconcentrations in Japanese patients with non-insulin-dependent diabetes mellitus: effect ofparenteral methylcobalamin treatment.Atherosclerosis 1993;103:149-157.

101. Vaccaro O, Ingrosso D, Rivellese A, et al.Moderate hyperhomocysteinaemia andretinopathy in insulin-dependent diabetes.Lancet 1997;349:1102-1103 [letter].

102. Neugebauer S, Baba T, Kurokawa K,Watanabe T. Defective homocysteine metabo-lism as a risk factor for diabetic retinopathy.Lancet 1997;349:473-474.

103. Roubenoff R, Dellaripa P, Nadeau MR, et al.Abnormal homocysteine metabolism inrheumatoid arthritis. Arthritis Rheum1997;40:718-722.

104. Krogh Jensen M, Ekelund S, Svendsen L.Folate and homocysteine status andhaemolysis in patients treated withsulphasalazine for arthritis. Scand J Clin LabInvest 1996;56:421-429.

105. Kang SS, Wong PW, Glickman PB, et al.Protein-bound homocyst(e)ine in patients withrheumatoid arthritis undergoing D-penicil-lamine treatment. J Clin Pharmacol1986;26:712-715.

106. Dennis VW, Robinson K. Homocysteinemiaand vascular disease in end-stage renal disease.Kidney Int 1996;57:S11-S17.

107. Robinson K, Gupta A, Dennis V, et al.Hyperhomocysteinemia confers an indepen-dent increased risk of atherosclerosis in end-stage renal disease and is closely linked toplasma folate and pyridoxine concentrations.Circulation 1996;94:2743-2748.

108. Barak AJ, Beckenhauer HC, Tuma DJ.Betaine, ethanol, and the liver: a review.Alcohol 1996;13:395-398.

109. Barak AJ, Beckenhauer HC, Tuma DJ. Betaineeffects on hepatic methionine metabolismelicited by short-term ethanol feeding. Alcohol1996;13:483-486.

110. Malinow MR, Levenson J, Giral P, et al. Roleof blood pressure, uric acid, andhemorheological parameters on plasmahomocyst(e)ine concentration. Atherosclerosis1995;114:175-183.

111. Coull BM, Malinow MR, Beamer N, et al.Elevated plasma homocyst(e)ine concentrationas a possible independent risk factor for stroke.Stroke 1990;21:572-576.

112. Gershon SL, Fox IH. Pharmacologic effects ofnicotinic acid on human purine metabolism.Lab Clin Med 1974;84:179-186.

113. Garg R, Malinow R, Pettinger M, et al.Treatment with niacin increases plasmahomocyst(e)ine levels. Circulation 1996;94(Suppl 1):I-457. [abstract]

114. Basu TK, Mann S. Vitamin B-6 normalizes thealtered sulfur amino acid status of rats fed dietscontaining pharmacological levels of niacinwithout reducing niacin’s hypolipidemiceffects. J Nutr 1997;127:117-121.

115. Tamburrini O, Bartolomeo-De Iuri A, AndriaG, et al. Bone changes in homocystinuria inchildhood. Radiol Med 1984;70:937-942.

116. Kaur M, Kabra M, Das GP, et al. Clinical andbiochemical studies in homocystinuria. IndianPediatr 1995;32:1067-1075.

117. Lubec B, Fang-Kircher S, Lubec T, et al.Evidence for McKusick’s hypothesis ofdeficient collagen cross-linking in patientswith homocystinuria. Biochim Biophys Acta1996;1315:159-162.

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Homocysteine Metabolism: Nutritional Modulation and Impact on … · 2019-09-20 · sulfuration pathway of homocysteine. This degradation pathway involves a two-step pro-cess resulting