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ARSENICALS INHIBIT THIOREDOXIN REDUCTASE ACTIVITY IN CULTURED RAT HEPATOCYTES
Citation:
Lin, S., L. M. Del Razo, M. Styblo, C. Wang, W. R. Cullen, AND D J. Thomas. ARSENICALS INHIBIT THIOREDOXIN REDUCTASE ACTIVITY IN CULTURED RAT HEPATOCYTES. Presented at SOT, San Francisco, CA, March 25 - 29, 2001.
Description:
ARSENICALS INHIBIT THIOREDOXIN REDUCTASE ACTIVITY IN CULTURED RAT HEPATOCYTES.
S. Lin1, L. M. Del Razo1, M. Styblo1, C. Wang2, W. R. Cullen2, and D.J. Thomas3. 1Univ. North Carolina, Chapel Hill, NC; 2Univ. British Columbia, Vancouver, BC, Canada; 3National Health and Environmental Effects Research Laboratory, ORD, U.S. E PA, Research Triangle Park, NC
Thioredoxin reductase (TR) plays an important role in cellular response to oxidative stress. Trivalent arsenicals, particularly methyl As containing trivalent arsenic (MAsIII), are potent inhibitors of purified mouse liver TR. MAsIII, a product of the biomethylation of As, was postulated to inhibit TR activity in cultured rat hepatocytes. Exposure to inorganic AsIII (iAsIII), MAsIII, or aurothioglucose (ATG, a competitive inhibitor of TR activity) for 30 minutes caused concentration-dependent reductions in TR activity. In cells exposed to 1 M MAsIII for up to 24 hours, inhibition of TR activity was greatest (~ 40%) after 15 minutes of exposure. After 3 hours exposure (when most MAsIII was converted to dimethyl As (DMAs)), TR activity returned to control levels. TR activity was unaffected by exposure to 50 M DMAsIII. In cells exposed to 10 M iAsIII, inhibition of TR activity was progressive; at 24 hours activity was reduced ~ 35%. Following exposure to iAsIII or MAsIII, the extent of inhibition of TR activity correlated strongly with the intracellular concentration of MAs. These results suggest arsenicals formed in the course of cellular metabolism of As are potent inhibitors of TR activity. Because MAsIII is an especially potent inhibitor of TR, the capacity of cells to produce or consume the intermediates in the pathway for As methylation may be an important determinant of susceptibility to the toxic effects of As. (This abstract does not necessarily reflect policy of the U.S. Environmental Protection Agency.)