The Cellular Metabolism and Systemic Toxicity of Arsenic
David J. Thomas,*
Miroslav Styblo,† and Shan Lin‡
*Pharmacokinetics Branch, Experimental Toxicology Division, National Health and Environmental Effects Research Laboratory, Ofﬁce of Research and
Development, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina 27711; †Department of Pediatrics, School of Medicine,
and Department of Nutrition, School of Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27514;
and ‡Curriculum in Toxicology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27514
Received February 22, 2001; accepted July 3, 2001
The Cellular Metabolism and Systemic Toxicity of Arsenic.
Thomas, D. J., Styblo, M., and Lin, S. (2001). Toxicol. Appl.
Pharmacol. 176, 127–144.
Although it has been known for decades that humans and many
other species convert inorganic arsenic to mono- and dimethylated
metabolites, relatively little attention has been given to the biolog-
ical effects of these methylated products. It has been widely held
that inorganic arsenicals were the species that accounted for the
toxic and carcinogenic effects of this metalloid and that methyl-
ation was properly regarded as a mechanism for detoxiﬁcation of
arsenic. Elucidation of the metabolic pathway for arsenic has
changed our understanding of the signiﬁcance of methylation.
Both methylated and dimethylated arsenicals that contain arsenic
in the trivalent oxidation state have been identiﬁed as intermedi-
ates in the metabolic pathway. These compounds have been de-
tected in human cells cultured in the presence of inorganic arsenic
and in urine of individuals who were chronically exposed to
inorganic arsenic. Methylated and dimethylated arsenicals that
contain arsenic in the trivalent oxidation state are more cytotoxic,
more genotoxic, and more potent inhibitors of the activities of
some enzymes than are inorganic arsenicals that contain arsenic in
the trivalent oxidation state. Hence, it is reasonable to describe the
methylation of arsenic as a pathway for its activation, not as a
mode of detoxiﬁcation. This review summarizes the current
knowledge of the processes that control the formation and fate of
the methylated metabolites of arsenic and of the biological effects
of these compounds. Given the considerable interest in the dose–
response relationships for arsenic as a toxin and a carcinogen,
understanding the metabolism of arsenic may be critical to assess-
ing the risk associated with chronic exposure to this element.
© 2001 Academic Press
Key Words: arsenic; inorganic arsenic; methylated arsenicals;
dimethylated arsenicals; metabolism; human; rat; mouse.
Chronic exposure to arsenic (As)
causes a wide range of
toxic effects and this metalloid is classiﬁed as a carcinogen in
humans (International Agency for Research on Cancer, 1987).
Long-term occupational exposure to As has been associated
with increased prevalences of cancer of the buccal cavity,
pharynx, lung, kidney, bone, large intestine, and rectum (En-
terline et al., 1995). Environmental exposures to inorganic As
commonly occur through the consumption of drinking
Disclaimer—This manuscript has been reviewed in accordance with the
policy of the Health Effects Research Laboratory, U.S. Environmental Protec-
tion Agency, and approved for publication. Approval does not signify that the
contents necessarily reﬂect the views and policies of the Agency, nor does
mention of trade names or commercial products constitute endorsement or
recommendation for use.
To whom correspondence should be addressed at MD 74, NHEERL,
ORD, U.S. EPA, Research Triangle Park, NC 27711. E-mail: thomas.
The nomenclature of arsenicals is often bewildering. Although other naming
schemes exist, current usage in the toxicological literature (e.g., Aposhian et al.,
2000a; Le et al., 2000a; Mandal et al., 2001) identiﬁes CH
(mono)methylarsonic acid, CH
as (mono)methylarsonous acid, (CH
(ϭO)OH as dimethylarsinic acid, and (CH
OH as dimethylarsinous
acid. In this review, we follow this convention for the naming of arsenicals used
by investigators in their studies. At the ﬁrst appearance for any compound, its
chemical formula is given. The abbreviations used to identify arsenicals that
contain As in the trivalent or pentavalent oxidation state are arsenate, iAs
; (mono)methylarsonic acid, MMA
ous acid, MMA
; dimethylarsinic acid, DMA
; and dim-
ethylarsinous acid, DMA
. It should be noted that current analytical
techniques that provide information on the speciation (i.e., oxidation state of As)
of inorganic and methylated arsenicals in biological matrices do not provide
additional information on the nature of the compounds with which these arsenicals
are associated. For example, it is suspected that a signiﬁcant fraction of MAs
cells is associated with speciﬁc proteins, likely through thiol and dithiol linkages.
However, the techniques for speciation analysis that determine the amounts of
in tissues do not provide additional information on the identity of the
ligands with which the arsenical is associated. Here, we use the common shorthand
of referring to MAs
, and others without implying any additional infor-
mation concerning the chemical species that contains these arsenicals. In those
cases in which the oxidation state of an arsenical in a biological sample has not
been determined, we use the generic abbreviations iAs, MAs, and DMAs.
Abbreviations used: inorganic As, iAs; maximum contaminant level, MCL;
methyl As, MAs; dimethyl As, DMAs; glutathione, GSH; arsenotriglutathione,
; S-adenosylmethionine, AdoMet; 2,3-dimercaptopropane-1-sul-
fonic acid, DMPS; hydride generation-atomic absorption spectrometry, HG-
AAS; concentration reducing cell viability by 50%, IC50; buthionine sulfoxi-
mine, BSO; GSH reductase, GR; GSH disulﬁde, GSSG; MAs
Toxicology and Applied Pharmacology 176, 127–144 (2001)
doi:10.1006/taap.2001.9258, available online at http://www.idealibrary.com on
Copyright © 2001 by Academic Press
All rights of reproduction in any form reserved.