Superfund Research Program
Diversity of Inorganic Arsenic Metabolism
Inorganic arsenic is an important environmental toxicant that is released from both natural and anthropogenic sources. It enters the environment not only from a variety of industrial processes, but also from geological materials such as rocks and minerals. Epidemiological evidence has associated chronic inorganic arsenic exposure with the development of skin, liver, lung and bladder cancer in humans. With an increasing number of people throughout the world being exposed to high levels of inorganic arsenic in drinking water, it is becoming increasingly important to understand the underlying causes of arsenic-induced diseases so that better preventive and treatment measures can be developed. However, an appropriate animal model with which to investigate this carcinogen is lacking, which has greatly hindered our understanding of its mechanisms of action.
One complication in studying the health effects of inorganic arsenic is that different species of animals appear to have different ways of processing this metalloid to less toxic forms. Many mammals, including humans, contain enzymes known as arsenic methyltransferase(s) that metabolize inorganic arsenic (arsenite, specifically) to methyl- and dimethyl-arsenical compounds. Because these methylated forms are less acutely toxic and more readily excreted than inorganic arsenic, methylation has been classically believed to be the primary mechanism of detoxification for inorganic arsenic. However, recent studies show that some mammals, including the guinea pig and chimpanzee, may be incapable of methylating inorganic arsenic, because they either lack or are deficient in arsenic methyltransferase(s). This suggests alternate detoxification pathways, such as protein binding, exist for inorganic arsenic.
Unique patterns of arsenic metabolism are also beginning to emerge within human populations. However, it is unclear at this time whether these different responses are due to environmental, genetic, nutritional or other factors. An understanding of the variability of inorganic arsenic metabolism within the phylogenetic Order Primates, man's closest genetic relatives, may provide data to better relate what environmental components may influence the carcinogenicity of inorganic arsenic in humans.
Researchers at the University of Arizona have been studying the biological molecules that are involved in the metabolism of inorganic arsenic within the Order Primates. To date, investigations of in vitro metabolism have been performed with hepatic tissue from 31 animals representing 17 different species of non-human primates and including species from both higher and lower primates in evolutionary classification.
A significant finding of these studies is that hepatic arsenite methyltransferase activity was not detected in 13 species. Many New World animals lacked this activity including the marmoset, squirrel monkey and tamarin, which are from regions of South America where water runoff from volcanic ash has a high content of arsenic. This finding suggests that these animals may have some other mechanism(s) to decrease arsenic toxicity and that high exposure to arsenic plus lack of these arsenic-detoxifying steps may have some evolutionary importance that helped these animals survive as a species.
The four species of monkeys that had hepatic arsenite methyltransferase activity include three from the Old World genus Macaca and one from the New World genus Saimiri. There appears to be a phylogenic component of a primate having arsenite methyltransferase activity as evidenced by the grouping of the three Macaca species. This suggests that within a given genus scientists may be able to predict the presence or deficiency of arsenite methyltransferase activity by screening one or more of its members. However, because of the difficulty in obtaining reliable hepatic tissue from more than one animal per species for many of the genera in the present study, additional efforts are ongoing to confirm these statements.
Another significant observation is the indication that animals of the same species may have slightly different forms of arsenite methyltransferase. Known as "genetic polymorphism," this phenomenon may explain why humans in a remote region of Chile do not appear to develop arsenic-induced cancer after generations of exposure, while residents of Taiwan, India and Mexico who have been exposed to arsenic during this generation exhibit symptoms of severe arsenic toxicity.
Currently, arsenite methyltransferase and other biological components involved in inorganic arsenic metabolism are being purified from non-primate sources. The amino acid sequence of arsenite methyltransferase is being determined for the development of genetic probes with which to further investigate the diversity of its enzymatic activities within the Order Primates, as well as in other animal Orders. Another aim in constructing these probes is for screening human populations to identify individuals who may have an increased susceptibility to develop arsenic-induced cancer.
Understanding the biochemical processes involved in inorganic arsenic metabolism may allow researchers to selectively inhibit or reduce the formation of the carcinogenic forms of arsenic, or induce their metabolism to a less toxic species. If there are genetic or ethnic differences in the catalysts that detoxify toxic arsenic substances in humans, then new and different regimens for treating people with arsenic poisoning may need to be devised. The identification of a number of animal species which do not appear capable of methylating inorganic arsenic suggests alternative detoxification mechanisms for this toxic metalloid exist and need to be investigated.
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To learn more about this research, please refer to the following sources:
- Healy SM, Wildfang E, Zakharyan RA, Aposhian HV. 1999. Diversity of inorganic arsenite biotransformation. Biol Trace Elem Res 68(3):249-266. PMID:10328340
- Wildfang E, Zakharyan RA, Aposhian HV. 1998. Enzymatic methylation of arsenic compounds: VI. Characterization of hamster liver arsenite and monomethylarsonic acid methyltransferase activities in vitro. Toxicol Appl Pharmacol 152(2):366-375. PMID:9853005
- Aposhian HV. 1997. Enzymatic methylation of arsenic species and other new approaches to arsenic toxicity. Annu Rev Pharmacol Toxicol 37:397-419. PMID:9131259
- Zakharyan RA, Wildfang E, Aposhian HV. 1996. Enzymatic methylation of arsenic compounds: III. The marmoset and tamarin, but not the rhesus, monkeys are deficient in methyltransferases that methylate inorganic arsenic. Toxicol Appl Pharmacol 140(1):77-84. PMID:8806872
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