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Tracking the pathway of arsenic metabolism
Citation:
THOMAS, D. J. Tracking the pathway of arsenic metabolism. Presented at Chemical Society of Canada Meeting, Edmonton, AB, CANADA, May 24 - 28, 2008.
Impact/Purpose:
This abstract describes research on the role of metabolism in the actions of arsenic as a toxicant and a carcinogen. Emphasis is placed on the relation between metabolic transformation of arsenic and its diverse activities in biological systems.
Description:
Although the toxic and carcinogenic properties of arsenic have been recognized for centuries, only in the past few decades has research focused on understanding the metabolic fate of arsenic in humans and relating metabolism to adverse health effects. In humans, conversion of inorganic arsenic to methylated species was definitively shown about thirty years ago. Initially, formation of methylated arsenicals was termed a detoxification process. However, because methylated metabolites containing arsenic in the trivalent oxidation state are more reactive and toxic than arsenite, methylation of inorganic arsenic should be considered an activation process. The simultaneous presence in cells of many metabolites of inorganic arsenic has made it difficult to determine which of the many molecular processes disturbed by these metabolites accounts for a specific toxic effect. Work with in vitro systems has provided data on some modes of action by which inorganic arsenic or its methylated metabolites can alter cellular functions (e.g., cell signaling). Studies with cloned human arsenic (+3 oxidation state) methyltransferase have elucidated molecular processes involved in methylation reactions and the factors which influence the pattern of methylated metabolites produced from inorganic arsenic. Improved analytical methods have provided new data needed to characterize the dosimetry of important metabolites. Integration of dosimetric data and estimates of kinetic parameters for methylation reactions support development and refinement of pharmacokinetic models that provide dose metrics for studies of the modes of action for various metabolites. Development of a comprehensive budget for all metabolites of inorganic arsenic will support improved dosimetry and foster better studies of the modes of action for arsenic as a toxicant and carcinogen in humans.