EPA Science Inventory

THE CELLUAR METABOLISM OF ARSENIC

Citation:

Thomas, D J. THE CELLUAR METABOLISM OF ARSENIC. Presented at US-Chile Conf. on Toxicogenomics, Santiago, Chile, Sept 29-Oct 2, 2002.

Description:

Because the methylation of arsenic produces intermediates and terminal products that exceed inorganic arsenic in potency as enzyme inhibitors, cytotoxins, and genotoxins, the methylation of arsenic is properly regarded as an activation process. The methylation of arsenic is an enzymatically-catalyzed process that yields methylated and dimethylated arsenic. Although the preferred substrates for purified arsenic methyltransferases contain arsenic in the trivalent oxidation state, the methylation of arsenic is an oxidative process that converts trivalent arsenic into pentavalent arsenic. Hence, pentavalent arsenicals must be reduced to trivalency to permit their use as substrates for methylation reactions. Reduction may be accomplished chemically by the oxidation of glutathione or it may be an enzymatically-catalyzed reaction. At least two enzymes have been identified as potential reductases for pentavalent arsenicals and these proteins may act in tandem with arsenic methyltransferases to catalyze all the steps in the methylation pathway. In addition, a recently-identified arsenic methyltransferase (cyt19) catalyzes both the oxidative methylation and the reduction of pentavalent arsenicals. Dithiothreitol and tris-(2-carboxyethyl)phosphine are approximately equipotent as reductants in reactions catalyzed by cyt19. A thioredoxin-thioredoxin reductase generation system also functions as a reductant for the cyt19-catalyzed methylation of arsenic. Because thioredoxin reductase in inhibited by methylated arsenicals produced by cellular metabolism of arsenic and thioredoxin is a candidate endogenous reductant for this reaction, there are now two links between the metabolism of arsenic and the thioredoxin-thioredoxin reductase cycle. Understanding the linkage between the regulation of thioredoxin reduction and the function of reduced thioredoxin as a critical reductant in the enzymatically-catalyzed methylation of arsenic may provide new insights into the role of the metabolism of arsenic in its actions as a toxin and carcinogen. (This abstract does not necessarily reflect EPA policy

Record Details:

Record Type: DOCUMENT (PRESENTATION/ABSTRACT)
Start Date: 09/29/2002
Completion Date: 09/29/2002
Record Last Revised: 06/06/2005
Record Created: 09/26/2003
Record Released: 09/26/2003
Record ID: 59610

Organization:

U.S. ENVIRONMENTAL PROTECTION AGENCY

OFFICE OF RESEARCH AND DEVELOPMENT

NATIONAL HEALTH AND ENVIRONMENTAL EFFECTS RESEARCH LAB

EXPERIMENTAL TOXICOLOGY DIVISION

PHARMACOKINETICS BRANCH