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Arsenite medicinal use, metabolism,pharmacokinetics and monitoring in human

hair

Article in Biochimie July 2009

Impact Factor: 2.96 DOI: 10.1016/j.biochi.2009.06.003 Source: PubMed

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4 authors, including:

Ioannis Nicolis

Universit Ren Descartes - Paris 5

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Emmanuel Curis


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Patrick Deschamps


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Available from: Emmanuel Curis

Retrieved on: 24 May 2016
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Mini-review

Arsenite medicinal use, metabolism, pharmacokinetics and monitoringin human hair

I. Nicolis*, E. Curis, P. Deschamps, S. Benazeth

Laboratoire de Biomathematiques, EA 2498, Departement de Sante Publique et Biostatistiques, Plateau iB2, Facultede Pharmacie, Universite Paris Descartes, Paris, FranceQ1

a r t i c l e i n f o

Article history:

Received 6 March 2009

Accepted 4 June 2009

Available online xxx

Keywords:

Hair

Arsenic

Speciation

Synchrotron induced X-ray fluorescence

Acute promyelocytic leukaemia

a b s t r a c t

Acute promyelocytic leukaemia (APL) is a distinctive subtype of acute myeloid leukaemias. Even through

this human disease can be treated by the intravenous administration of all-trans retinoic acid (ATRA),

25% of patients typically relapse after the first treatment. In this context, the intravenous administration

of APL patients with an aqueous solution of arsenic trioxide has also been demonstrated to be successful

despite the established mammalian toxicity of this arsenic compound. Accordingly, the administration of

a therapeutic dose of arsenic trioxide has resulted in an improved patient survival in both relapsing as

well newly diagnosed APL patients.

We present here a mini-review of the medicinal use of arsenite, its mammalian metabolism (with an

emphasis on biomethylation pathways), its elimination and pharmacokinetics and the novel application

of hair analysis as a biomonitoring material. This mini-review also introduces our own results on the

analysis of hair of patients receiving arsenic trioxide therapy.

In this work, instead of quantifying arsenic content in bulk hair, we performed longitudinal analysis in

order to use hair as a marker of arsenic exposure correlated to a time scale. Taking into account the hair

growth rate, the longitudinal analysis of hair is demonstrated to provide a chronological record of the

treatment of patients with arsenic trioxide. The small quantity of material to be analysed required the use

of Synchrotron radiation based X-ray fluorescence (SXRF) spectroscopy. The hair arsenic content was well

correlated with the clinical background of patients and reflected the intake of arsenic trioxide. Inparticular, the onset of arsenic trioxide therapy and interruptions during therapy were reflected by total

arsenic content, which suggested rapid elimination.

Another type of experiment, micro-XRF cartography on thin hair slices, allowed us to obtain distri-

bution maps of arsenic, which demonstrated that arsenic is located at the periphery of hair. Micro-XANES

spectra recorded at the periphery of hair, suggest that inorganic arsenic is incorporated in hair in its

trivalent oxidation state, in agreement with previous results.

2009 Published by Elsevier Masson SAS.

1. Introduction

Leukaemias account for over 3% of total cancer mortality in

Europe and North America. [1] Acute promyelocytic leukaemia

(APL) is a distinctive subtype of acute myeloid leukaemias (AML),which represents approximately 1015% of adult AML.[2]Since the

late 80s, APLis treated by a combination of standard chemotherapy

with all-trans retinoic acid (ATRA). Since the late 90s, however,

injectable aqueous arsenic trioxide[36]has been also successfully

used for the treatmentof relapsing APL patients and, more recently,

in newly diagnosed patients.

Our group, in collaboration with researchers located in several

Paris hospitals, works on the stability and bioavailability of nutri-

tional supplements and medicinal drugs, such as arsenite to treat

leukaemia. Using EXAFS (Extended X-Ray Absorption Fine Struc-

ture) and XANES (X-ray Absorption Near Edge Structure)spectroscopies, we previously established that arsenious acid

[As(OH)3] is the only detectable molecular form present in the

injectable solution of arsenic trioxide. In the aim to study the

assimilation and elimination of the drug after administration, we

obtained hairs of two patients having received the arsenic therapy.

As the hair stores the trace elements from blood[7]arsenic expo-

sure can be followed along the hair before, during and after the

treatment period.

In a first step of the study, we performed Synchrotron based

X-ray fluorescence (SXRF) experiments in the LURE French

synchrotron facility, following thus the arsenic content along hairs* Corresponding author. Tel.: 33 153739778; fax: 33 153739777.

E-mail address: [email protected](I. Nicolis).

Contents lists available atScienceDirect

Biochimie

j o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m / l o c a t e / b i o c h i

ARTICLE IN PRESS

0300-9084/$ see front matter 2009 Published by Elsevier Masson SAS.

doi:10.1016/j.biochi.2009.06.003

Biochimie xxx (2009) 18

BIOCHI3133_proof 18 June 2009 1/8

Please cite this article in press as: I. Nicolis et al., Arsenite medicinal use, metabolism, pharmacokinetics and monitoring in human hair, Bio-chimie (2009), doi:10.1016/j.biochi.2009.06.003
https://www.researchgate.net/publication/14089381_Chen_GQ_Shi_XG_Tang_W_Xiong_SM_Zhu_J_Cai_X_et_al_Use_of_arsenic_trioxide_As2O3_in_the_treatment_of_acute_promyelocytic_leukemia_APL_I_As2O3_exerts_dose-dependent_dual_effects_on_APL_cells_Blood_89_334?el=1_x_8&enrichId=rgreq-4d92e61f-24a5-4047-8409-89b9b4cfc5cc&enrichSource=Y292ZXJQYWdlOzI2MjkzMzA2O0FTOjEwMzczMjIyNjI5Nzg2NEAxNDAxNzQzMDk4NTUyhttp://-/?-https://www.researchgate.net/publication/12258654_Trends_in_mortality_from_leukemia_in_subsequent_age_groups?el=1_x_8&enrichId=rgreq-4d92e61f-24a5-4047-8409-89b9b4cfc5cc&enrichSource=Y292ZXJQYWdlOzI2MjkzMzA2O0FTOjEwMzczMjIyNjI5Nzg2NEAxNDAxNzQzMDk4NTUyhttps://www.researchgate.net/publication/13485910_Complete_Remission_after_Treatment_of_Acute_Promyelocytic_Leukemia_with_Arsenic_Trioxide?el=1_x_8&enrichId=rgreq-4d92e61f-24a5-4047-8409-89b9b4cfc5cc&enrichSource=Y292ZXJQYWdlOzI2MjkzMzA2O0FTOjEwMzczMjIyNjI5Nzg2NEAxNDAxNzQzMDk4NTUyhttps://www.researchgate.net/publication/13485910_Complete_Remission_after_Treatment_of_Acute_Promyelocytic_Leukemia_with_Arsenic_Trioxide?el=1_x_8&enrichId=rgreq-4d92e61f-24a5-4047-8409-89b9b4cfc5cc&enrichSource=Y292ZXJQYWdlOzI2MjkzMzA2O0FTOjEwMzczMjIyNjI5Nzg2NEAxNDAxNzQzMDk4NTUyhttps://www.researchgate.net/publication/14089381_Chen_GQ_Shi_XG_Tang_W_Xiong_SM_Zhu_J_Cai_X_et_al_Use_of_arsenic_trioxide_As2O3_in_the_treatment_of_acute_promyelocytic_leukemia_APL_I_As2O3_exerts_dose-dependent_dual_effects_on_APL_cells_Blood_89_334?el=1_x_8&enrichId=rgreq-4d92e61f-24a5-4047-8409-89b9b4cfc5cc&enrichSource=Y292ZXJQYWdlOzI2MjkzMzA2O0FTOjEwMzczMjIyNjI5Nzg2NEAxNDAxNzQzMDk4NTUyhttps://www.researchgate.net/publication/12747874_Niu_C_Yan_H_Yu_T_Sun_HP_Liu_JX_Li_XS_Wu_W_Zhang_FQ_Chen_Y_Zhou_L_Li_JM_Zeng_XY_Yang_RR_Yuan_MM_Ren_MY_Gu_FY_Cao_Q_Gu_BW_Su_XY_Chen_GQ_Xiong_SM_Zhang_T_Waxman_S_Wang_ZY_Chen_Z_Hu_J_Shen_ZX_Chen_SJStudi?el=1_x_8&enrichId=rgreq-4d92e61f-24a5-4047-8409-89b9b4cfc5cc&enrichSource=Y292ZXJQYWdlOzI2MjkzMzA2O0FTOjEwMzczMjIyNjI5Nzg2NEAxNDAxNzQzMDk4NTUyhttps://www.researchgate.net/publication/12005851_Clinical_Experience_of_Arsenic_Trioxide_in_Relapsed_Acute_Promyelocytic_Leukemia?el=1_x_8&enrichId=rgreq-4d92e61f-24a5-4047-8409-89b9b4cfc5cc&enrichSource=Y292ZXJQYWdlOzI2MjkzMzA2O0FTOjEwMzczMjIyNjI5Nzg2NEAxNDAxNzQzMDk4NTUyhttp://-/?-mailto:[email protected]://www.sciencedirect.com/science/journal/03009084http://www.elsevier.com/locate/biochihttps://www.researchgate.net/publication/13485910_Complete_Remission_after_Treatment_of_Acute_Promyelocytic_Leukemia_with_Arsenic_Trioxide?el=1_x_8&enrichId=rgreq-4d92e61f-24a5-4047-8409-89b9b4cfc5cc&enrichSource=Y292ZXJQYWdlOzI2MjkzMzA2O0FTOjEwMzczMjIyNjI5Nzg2NEAxNDAxNzQzMDk4NTUyhttps://www.researchgate.net/publication/12258654_Trends_in_mortality_from_leukemia_in_subsequent_age_groups?el=1_x_8&enrichId=rgreq-4d92e61f-24a5-4047-8409-89b9b4cfc5cc&enrichSource=Y292ZXJQYWdlOzI2MjkzMzA2O0FTOjEwMzczMjIyNjI5Nzg2NEAxNDAxNzQzMDk4NTUyhttps://www.researchgate.net/publication/14089381_Chen_GQ_Shi_XG_Tang_W_Xiong_SM_Zhu_J_Cai_X_et_al_Use_of_arsenic_trioxide_As2O3_in_the_treatment_of_acute_promyelocytic_leukemia_APL_I_As2O3_exerts_dose-dependent_dual_effects_on_APL_cells_Blood_89_334?el=1_x_8&enrichId=rgreq-4d92e61f-24a5-4047-8409-89b9b4cfc5cc&enrichSource=Y292ZXJQYWdlOzI2MjkzMzA2O0FTOjEwMzczMjIyNjI5Nzg2NEAxNDAxNzQzMDk4NTUyhttps://www.researchgate.net/publication/12747874_Niu_C_Yan_H_Yu_T_Sun_HP_Liu_JX_Li_XS_Wu_W_Zhang_FQ_Chen_Y_Zhou_L_Li_JM_Zeng_XY_Yang_RR_Yuan_MM_Ren_MY_Gu_FY_Cao_Q_Gu_BW_Su_XY_Chen_GQ_Xiong_SM_Zhang_T_Waxman_S_Wang_ZY_Chen_Z_Hu_J_Shen_ZX_Chen_SJStudi?el=1_x_8&enrichId=rgreq-4d92e61f-24a5-4047-8409-89b9b4cfc5cc&enrichSource=Y292ZXJQYWdlOzI2MjkzMzA2O0FTOjEwMzczMjIyNjI5Nzg2NEAxNDAxNzQzMDk4NTUyhttps://www.researchgate.net/publication/12005851_Clinical_Experience_of_Arsenic_Trioxide_in_Relapsed_Acute_Promyelocytic_Leukemia?el=1_x_8&enrichId=rgreq-4d92e61f-24a5-4047-8409-89b9b4cfc5cc&enrichSource=Y292ZXJQYWdlOzI2MjkzMzA2O0FTOjEwMzczMjIyNjI5Nzg2NEAxNDAxNzQzMDk4NTUyhttp://www.elsevier.com/locate/biochihttp://www.sciencedirect.com/science/journal/03009084mailto:[email protected]://-/?-http://-/?-http://-/?-http://-/?-http://-/?-


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of patients first with a coarse 5 mm step [8,9]and after with a finer

3 mm step. These preliminary LURE experiments have been refined

in the ESRF European synchrotron facility, confirming correlations

between the therapy protocol and the hair content.

We present here a mini-review on arsenite medicinal use,

metabolism, pharmacokinetics and dosage in hair, followed by our

own results on hair analysis. Three types of measurements are

presented: fine step longitudinal hair X-ray fluorescence spec-

troscopy, transversal hair cartography by spatially resolved X-ray

fluorescence spectroscopy, and micro-XANES around the arsenic K-

edge (11 867 eV) on thin hair sections. Focalisation and intensity

achieved with synchrotron X-ray sources allows the analysis at the

micro scale. With these three experimental techniques we obtain

kinetic information on arsenic inclusion along hair, trace element

distribution perpendicularly to the hair axis and chemical specia-

tion of arsenic incorporated in hair.

2. Arsenic and cancer treatment

Arsenic is a well-known naturally occurring metalloid. The first

written reference of arsenics medical use goes back to the 5th

century B.C.: Hippocrates of Cos quotes, among other ointments for

wound healing, one containing a mixture of two sulphur arsenicals,orpiment and realgar.[10] The remedy is referenced as Caria

medication, which probably indicates that the formulation is even

older. However, it is not before Celsus on the 1st century of our era

that we found an explicit indication for arsenic used against solid

tumors.[11] Since then, arsenic has been empirically used for

various diseases, in particular after the introduction of the well-

known Fowler solution in 1788, a potassium bicarbonate-based

solution of arsenic trioxide. In 1878 the first report of white blood

cell decrease after administration of the Fowler solution has been

published, particularly including a chronic myelogenous leukemia

(CML) patient.[12] Consequently, arsenic trioxide based therapy

became the main antileukemic treatment until, first, the advent of

radiotherapy in 1903[13]and, later, the development of cytotoxic

chemotherapy in the second half of the 20th century. Despitereports of successful treatments during the 30s [14], serious

evidence about the chronic poisoning of treated patients [15]put

an end to arsenic medication against CML.

Acute promyelocytic leukaemia (APL) is characterised by a t(15;

17) (q22; q21) chromosome translocation (more than 95% of

patients) leading to the fusion of the RARa and PML genes.[16]The

PML-RARa chimeric protein inhibits normal myeloid differentiation

leading to an accumulation of the leukaemic cells at the promye-

locytic stage of development, severe coagulopathy and high early

mortality. In addition the PML-RARaprevents apoptosis. All-trans

retinoic acid (ATRA) degrades and cleaves the PML-RARa onco-

protein, leading thus to a significant increase of patient

survival.[1720] Nevertheless 25% of patients have a relapse after

the first treatment, leaving only bone marrow transplantation as anoption, although only for the younger relapsed patients.[2]

From the beginning of the 80s a Chinese group reported

successful use against APL of a mixture (referenced as Ai-lin I or

Ailing-1) containing arsenic and mercury in low doses[21,22]. This

report was followed by a detailed study of a pure arsenic trioxide

solution in intravenous infusion yielding complete remission for 9

among 10 patients.[3,4,23]Because of the well-established arsenic

toxicity, caution was initially suggested.[24]A subsequent US study

reported complete remission for 11 among 12 patients suffering

APL after arsenic trioxide administration.[2]This pilot study was

followed by a multicenter study on 40 relapsing APL patients, of

which 85% achieved complete remission.[25]The safety profile of

the drug is favourable at therapeutical doses and adverse events are

reversible.[6,26,27]

The mechanism of action is dual depending on dose. At high

concentrations it implies induced apoptosis in leukaemic cells

depending on the activity of the enzymes that regulate cellular

H2O2 content[3,23,28]. At lower doses it induces partial differen-

tiation of the myeloid cells.[29] Degradation of the PML-RARachimeric protein could contribute to both effects.[3032]

Treatment of relapsing APL with a 1 mg/mL arsenic trioxide

intravenously administered solution (Trisenox) has been

approved by the FDA in September 2000. All studies indicate an

improved patient survival and increased complete remissions for

both relapsing and newly diagnosed patients in particular in

combination with ATRA. Numerous studies in the last decade have

confirmed arsenic trioxide as a successful treatment for

APL.[20,3335] Arsenic trioxide and organic arsenic compounds are

tested also for other cancers as well [3639] and trials are per-

formed to adjust treatment to different age groups[40,41].

3. Arsenic metabolism

Arsenic metabolism is a subject of numerous studies as it

proceeds via a particularly complex pathway and has extensively

been studied in view of its toxicity.[4244]

In the past it was generally admitted that the methylation

pathway is a detoxification process as the methylated arsenic

compounds were considered less toxic than the inorganic arseni-

cals.[45,46] However, in the last decades many published studies

question this view [4749]. Indeed, evidence about the cytotoxicity

of methylated compounds appeared [50]. In particular, although

methylated arsenic (V) compounds are less toxic than inorganic

ones[51], the trivalent intermediates formed during the methyla-

tion process are much more toxic.[49,5153]Obviously the details

of the methylation pathway are highly relevant for an under-

standing of arsenic toxicity as well as of bioavailability in a thera-

peutic context.

While it has long been accepted that arsenic is metabolized via

a succession of oxidative methylation and reduction steps leading

from inorganic trivalent arsenic to pentavalent dimethylarsinicacid, recent studies proposed an alternative reductive methylation

pathway. We summarize hereafter the main characteristics of those

pathways.

3.1. Oxidative methylation pathway (Fig. 1)

The pioneering work of Challenger on biological methylation

[54], provided the first detailed view of the oxidative methylation

pathway. The main characteristic of this pathway is that only

trivalent arsenic compounds can be biomethylated, while

iAsV

arsenate

iAsIII

arsenite

MMAV

monomethylarsonic acidMMAIII

monomethylarsonous acid

DMAIII

dimethylarsinous acid

DMAV

dimethylarsinic acid

(cacodylic acid)

1.20.4.1

arsenate reductaseor

2.4.2.1purine nucleoside phosphorylase

1.20.4.2methylarsonate

reductase

2.1.1.137arsenite

methyltransferase

2.1.1.137arsenite

methyltransferase

dimethylarsinatereductase

Fig. 1. Arsenic oxidative methylation pathway.

I. Nicolis et al. / Biochimie xxx (2009) 182

ARTICLE IN PRESS BIOCHI3133_proof 18 June 2009 2/8

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OzI2MjkzMzA2O0FTOjEwMzczMjIyNjI5Nzg2NEAxNDAxNzQzMDk4NTUyhttps://www.researchgate.net/publication/8439340_A_clinical_and_pharmacological_study_of_arsenic_trioxide_in_advanced_multiple_myeloma_patients?el=1_x_8&enrichId=rgreq-4d92e61f-24a5-4047-8409-89b9b4cfc5cc&enrichSource=Y292ZXJQYWdlOzI2MjkzMzA2O0FTOjEwMzczMjIyNjI5Nzg2NEAxNDAxNzQzMDk4NTUyhttps://www.researchgate.net/publication/5885711_Phase_1_trial_and_pharmacokinetic_study_of_arsenic_trioxide_in_children_and_adolescents_with_refractory_or_relapsed_acute_leukemia_including_acute_promyelocytic_leukemia_or_lymphoma?el=1_x_8&enrichId=rgreq-4d92e61f-24a5-4047-8409-89b9b4cfc5cc&enrichSource=Y292ZXJQYWdlOzI2MjkzMzA2O0FTOjEwMzczMjIyNjI5Nzg2NEAxNDAxNzQzMDk4NTUyhttps://www.researchgate.net/publication/23951629_Treatment_of_elderly_adults_with_acute_promyelocytic_leukemia_Put_the_pedal_to_metal?el=1_x_8&enrichId=rgreq-4d92e61f-24a5-4047-8409-89b9b4cfc5cc&enrichSource=Y292ZXJQYWdlOzI2MjkzMzA2O0FTOjEwMzczMjIyNjI5Nzg2NEAxNDAxNzQzMDk4NTUyhttps://www.researchgate.net/publication/228761563_Styblo_M_Del_Razo_LM_Vega_L_et_al_Comparative_toxicity_of_trivalent_and_pentavalent_inorganic_and_methylated_arsenicals_in_rat_and_human_cells?el=1_x_8&enrichId=rgreq-4d92e61f-24a5-4047-8409-89b9b4cfc5cc&enrichSource=Y292ZXJQYWdlOzI2MjkzMzA2O0FTOjEwMzczMjIyNjI5Nzg2NEAxNDAxNzQzMDk4NTUyhttps://www.researchgate.net/publication/228761563_Styblo_M_Del_Razo_LM_Vega_L_et_al_Comparative_toxicity_of_trivalent_and_pentavalent_inorganic_and_methylated_arsenicals_in_rat_and_human_cells?el=1_x_8&enrichId=rgreq-4d92e61f-24a5-4047-8409-89b9b4cfc5cc&enrichSource=Y292ZXJQYWdlOzI2MjkzMzA2O0FTOjEwMzczMjIyNjI5Nzg2NEAxNDAxNzQzMDk4NTUyhttps://www.researchgate.net/publication/10710072_Combined_treatment_with_arsenic_trioxide_and_all-trans-retinoic_acid_in_patients_with_relapsed_acute_promyelocytic_leukemia?el=1_x_8&enrichId=rgreq-4d92e61f-24a5-4047-8409-89b9b4cfc5cc&enrichSource=Y292ZXJQYWdlOzI2MjkzMzA2O0FTOjEwMzczMjIyNjI5Nzg2NEAxNDAxNzQzMDk4NTUyhttp://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-http://-/?-


4/9

UNCORRE

CTEDPR

OOF

pentavalent ones have to be reduced first in order to undergo

further biomethylation. While Challenger suggested formaldehyde

as the methyl donor, it was later proved that S-adenosylmethionine

(SAM) is the methyl donor for the consecutive methylations.[55,56]

Several groups worked on the characterisation of the enzymes

involved in the biomethylation and reduction steps of the pathway

and two mechanisms are proposed.

The enzyme catalyzing the biomethylation has been identified

as arsenite methyltransferase (E.C. 2.1.1.137, also named Cyt19).[57]

It is a 375 amino acid cytoplasmic protein with an MW of 41748 Da

coded by the gene AS3MT located in chromosom 10.[58]The same

enzyme can use as substrate either inorganic arsenite (AsIII) to

methylate it towards monomethylarsonic acid (AsV) or mono-

methylasonous acid (AsIII) to methylate it towards dimethylarsinic

acid (AsV).[47,59] The arsenic metabolism pathway shares many

common features among prokaryotes and eukaryotes[60]; homo-

logues of Cyt19 protein, with a significant conservation of five

cysteine residues, have been found in a wide variety of species

attesting a well conserved function [61]. Nevertheless, some

species lack arsenite methyltransferase activity, mainly new world

animals with the noteworthy exception of chimpanzee, only old

world mammal not methylating arsenic[62]. It has been suggested

that this deficiency is an evolutionary advantage for animalsexposed to trypanosomal diseases, as the absence of methylation

maintains chemotherapeutic levels of arsenite in the animals blood

and liver.[47]

The oxidative methylation scheme described above, requires

reduction of the pentavalent arsenic species in order to proceed.

Several glutathione dependent enzymes have been proposed as

putative reductases for these reductions. The inorganic pentavalent

arsenate is reduced in bacteria by an arsenate reductase (E.C.

1.20.4.1) while in humans a glyceraldehyde-3-phosphate dehy-

drogenase has been reported working in vitro as arsenate reduc-

tase.[63] A methylarsonate reductase (E.C. 1.20.4.2) has been

proven in vitro in rabbit and hamster liver extracts to reduce

monomethylarsonic acid to monomethylasonous acid[64,65]and

has been identified as a glutathione-S-transferase omega(GSTO).[66]However, in GSTO knock out mice a reductase activity

remained, suggesting alternative pathways.[67]An other route for

reduction of arsenate to arsenite was identified, involving purine

nucleoside phosphorylase (E.C. 2.4.2.1) in the presence of dihy-

drolipoic acid. The hypothesis explaining this mechanism is that

since arsenate is chemically similar to phosphate, it can substitute

for phosphate, resulting in the formation of ribose-1-arsenate.[68]

Another proposition for the reduction steps of the pathway is that

both oxidative methylation and reduction activities are fused in the

same protein, arsenite methyltransferase. Indeed, it has been found

that in the presence of reducing agents, recombinant rat and

human arsenite methyltransferase could sustain the whole

pathway from inorganic arsenate to trimethylarsine oxide.[69] It

appears plausible that all these reduction mechanisms couldredundantly occurin vivo.[70]

3.2. Reductive methylation pathway (Fig. 2)

An alternative metabolic pathway has been recently proposed,

which proceeds by non-oxidative methylation, cancelling the need

for intermediate reduction steps.[71,72]Via this scheme, arsenate

needs still to be reduced to arsenite as exposed above but instead of

undergo oxidative methylation it forms an arsenic triglutathione

complex. This complex, substrate for arsenite methyltransferase,

can be methylated without oxidation directly to methylarsonic

diglutathione, which can be further methylated by the same arse-

nite methyltransferase to dimethylarsinic glutathione. At low

glutathione concentrations, both methylarsonic diglutathione and

dimethylarsinic glutathione are hydrolysed to trivalent mono-

methylarsonous and dimethylarsinous acids, further oxidized by

H2O2to monomethylarsonic and dimethylarsinic acids respectively

[73]. Interestingly, it is suggested that the glutathione complexes

are the arsenical compounds transported from the liver to the

blood stream and kidney and it has been found that both methyl-

arsonic diglutathione and dimethylarsinic glutathione are more

stable than arsenic triglutathione.[74]

4. Arsenic pharmacokinetics

All pharmacokinetic studies agree on the rapid kinetics of

arsenic metabolism and rapid decrease of arsenic species in blood

after intravenous administration at the FDA approved dose of

0.15 mg As2O3/kg body wt. During the first 24 h after adminis-

tration trivalent inorganic arsenite is the main compound found in

urine, while pentavalent metabolites monomethylarsonic and

dimethylarsinic acids become the major urine arsenic species after

the first 24 h, dimethylarsinic acid being generally the mostimportant one in percentage.[75,76] Only small amounts of

pentavalent inorganic arsenate are detected in urine. Because of

spontaneous oxidation of trivalent to pentavalent methylated

compounds, only recently the highly toxic monomethylarsonous

and dimethylarsinous acids have been detected in urine

samples.[75,7779]Contradictory results are published concerning

excretion routes. Urinary excretion is reported as a minor route for

elimination with 8% of daily dose by Shen et al.[4]but as a major

elimination route by Fukai et al.[76]which report 127% excretion of

the daily dose after repeated administrations. Other authors report

intermediate values ranging from 18%[80] to 65%[75] after intra-

venous administration or 4660% after oral ingestion[8185]. Oral

administration of As4S4 results in ca. 70% urinary excretion.[86]A

study of urinary excretion as a function of time on patientsreceiving daily intravenous doses of arsenite reports a urinary

excretion of 20% on the first day of therapy but maintained at 60%

after the first week.[87] It is noteworthy that large variations are

reported among individuals concerning arsenic methylation which

probably affect toxicity and response to therapy.[88]

In samples collected from patients for three weeks after the last

administration of remission induction therapy, blood cells arsenic

content was measured 610 times higher than plasma levels.[89]

Pentavalent arsenic is found in blood only transiently at the end of

therapy and rapidly disappears. [40,89] In one study pentavalent

arsenic is observed at higher concentrations [87] but this is possibly

an artefact as analyses have been performed five years after sample

collection (conserved at 20 C) and trivalent arsenic is known to

be oxidised to pentavalent even at 4

C after two months.[90]

iAsV

arsenate

iAsIII

arsenite

MMAV

monomethylarsonic

acid

MMAIII

monomethylarsonous

acid

DMAIII

dimethylarsinous acid

DMAV

dimethylarsinic acid

(cacodylic acid)

1.20.4.1

arsenatereductase

2.1.1.137

arsenite

methyltransferase

2.1.1.137

arsenite

methyltransferase

AIIITG

arsenic trigluthathione

GSH

MAIIIDG

methyl arsenic

digluthathione

DMAIIIG

dimethyl arsenic

gluthathione

GSH

GSH

Fig. 2. Arsenic reductive methylation pathway.

I. Nicolis et al. / Biochimie xxx (2009) 18 3

ARTICLE IN PRESS BIOCHI3133_proof 18 June 2009 3/8

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