Toxicological Sciences, Vol 49, 5-14, Copyright © 1999 by Society of Toxicology
PL Goering, HV Aposhian, MJ Mass, M Cebrian, BD Beck and MP Waalkes
Inorganic arsenic is considered a high-priority hazard, particularly
because of its potential to be a human carcinogen. In exposed human
populations, arsenic is associated with tumors of the lung, skin, bladder,
and liver. While it is known to be a human carcinogen, carcinogenesis in
laboratory animals by this metalloid has never been convincingly
demonstrated. Therefore, no animal models exist for studying molecular
mechanisms of arsenic carcinogenesis. The apparent human sensitivity,
combined with our incomplete understanding about mechanisms of carcinogenic
action, create important public health concerns and challenges in risk
assessment, which could be met by understanding the role of metabolism in
arsenic toxicity and carcinogenesis. This symposium summary covers three
critical major areas involving arsenic metabolism: its biodiversity, the
role of arsenic metabolism in molecular mechanisms of carcinogenesis, and
the impact of arsenic metabolism on human risk assessment. In mammals,
arsenic is metabolized to mono- and dimethylated species by
methyltransferase enzymes in reactions that require S-adenosyl- methionine
(SAM) as the methyl donating cofactor. A remarkable species diversity in
arsenic methyltransferase activity may account for the wide variability in
sensitivity of humans and animals to arsenic toxicity. Arsenic interferes
with DNA methyltransferases, resulting in inactivation of tumor suppressor
genes through DNA hypermethylation. Other studies suggest that
arsenic-induced malignant transformation is linked to DNA hypomethylation
subsequent to depletion of SAM, which results in aberrant gene activation,
including oncogenes. Urinary profiles of arsenic metabolites may be a
valuable tool for assessing human susceptibility to arsenic carcinogenesis.
While controversial, the idea that unique arsenic metabolic properties may
explain the apparent non-linear threshold response for arsenic
carcinogenesis in humans. In order to address these outstanding issues,
further efforts are required to identify an appropriate animal model to
elucidate carcinogenic mechanisms of action, and to define dose-response
relationships.
ARTICLES
The enigma of arsenic carcinogenesis: role of metabolism
Division of Life Sciences, Center for Devices and Radiological Health, Food and Drug Administration, Rockville, Maryland 20852, USA. plg@cdrh.fda.gov
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