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Role of Metabolism in Arsenic-Induced Toxicity: Identification and Quantification of Arsenic Metabolites in Tissues and Excreta
Citation:
ADAIR, B. AND M. F. HUGHES. Role of Metabolism in Arsenic-Induced Toxicity: Identification and Quantification of Arsenic Metabolites in Tissues and Excreta. Presented at 3RD Asian Pacific Regional Meeting of the International Society for the Study of Xenobiotics, Bangkok, THAILAND, June 09 - 12, 2009.
Impact/Purpose:
This abstract describes the methods used and results of several studies that analyzed the urine and tissues of rats and mice for metabolites of administered inorganic and methyl arsenic. Several metabolites have been identified and may have a role in arsenic-induced toxicity.
Description:
Arsenic is a known toxicant and carcinogen. Methylation of inorganic arsenic was once thought to be a detoxification mechanism because of the rapid excretion and relatively lower toxicity of the pentavalent organic arsenical metabolites. Advances in analytical chemistry have allowed identification and quantification of trivalent organic arsenical metabolites that have proven to be potent toxicants. Thus, it appears that the metabolism of arsenic involves toxic activation via reduction of pentavalent to trivalent arsenicals and detoxification via oxidative methylation of trivalent to pentavalent arsenicals. Multiple analytical techniques are necessary for accurate identification and quantification of arsenic metabolites. Our research group has used hydride generation- atomic absorption spectrometry with cryogenic trapping to detect trivalent arsenicals in urine and pentavalent arsenicals in urine and tissues such as liver, lung, and bladder of arsenic-treated rodents. In addition, HPLC-inductively coupled plasma-mass spectrometry and HPLC-electrospray ionization-mass spectrometry have been used to quantify and identify thiolated arsenicals in urine, respectively. Mouse and rat metabolism studies with oral administration of arsenicals revealed that the metabolites produced differed by methylation and oxidation state of the arsenicals administered. Metabolites detected in mice following monomethyl arsenic exposure include dimethyl and trimethyl arsenic, with ease of methylation being greater for trivalent monomethyl arsenic. Mice metabolized dimethyl arsenic to produce trimethyl and thiolated arsenicals in urine. In the rat, following a 14-day drinking water exposure to pentavalent dimethyl arsenic, metabolites included trimethyl and thiolated arsenicals in urine and trimethylarsenic in tissues. Following a similar exposure of rats to arsenate, metabolites in urine included dimethyl, trimethyl and thiolated arsenicals, and dimethyl and trimethyl arsenicals were detected in tissues. The acute and chronic toxicities of this metalloid may be from one or more of these metabolites of inorganic arsenic. Therefore, it is critical to link results from metabolism and health effect studies to determine the mode of action for arsenic toxicity. (Disclaimer: This abstract does not necessarily reflect EPA policy.)