@article {5130,
	title = {Arsenicals inhibit thioredoxin reductase in cultured rat hepatocytes},
	journal = {Chemical Research in Toxicology},
	volume = {14},
	number = {3},
	year = {2001},
	note = {ISI Document Delivery No.: 415LTTimes Cited: 86Cited Reference Count: 46},
	month = {Mar},
	pages = {305-311},
	type = {Article},
	abstract = {Thioredoxin reductase (TR), an NADPH-dependent flavoenzyme that catalyzes the reduction of many disulfide-containing substrates, plays an important role in the cellular response to oxidative stress. Trivalent arsenicals, especially methyl As that contains trivalent arsenic (MAsIII), are potent noncompetitive inhibitors of TR purified from mouse liver. Because MAsIII is produced in the biomethylation of As, it was postulated that the extent of inhibition of TR in cultured rat hepatocytes would correlate with the intracellular concentration of methyl As. Exposure of cultured hepatocytes to inorganic As-III (iAs(III)), MAsIII, or aurothioglucose (ATG, a competitive inhibitor of TR activity) for 30 min caused a concentration-dependent reduction in TR activity. The estimated IC50 was much greater than 100 muM for iAS(III), similar to 10 muM for ATG, and similar to3 muM for MAsIII. In hepatocytes exposed to 1 muM MAsIII for up to 24 h, the inhibition of TR activity was maximal (similar to 40\%) after exposure for 15 min. After exposure for 3 h [when most MAsIII has been converted to dimethyl As (DMAs)], TR activity in these cells had returned to control levels. Notably, exposure of the cell to 50 muM DMAsIII did not affect TR activity. In hepatocytes exposed to 10 muM iAs(III) for up to 24 h, the inhibition of TR activity was progressive; at 24 h, activity was reduced similar to 35\%. Following exposure to iAsIII or MAsIII, the extent of inhibition of TR activity correlated strongly with the intracellular concentration of MAs. Taken together, these results suggest that arsenicals formed in the course of cellular metabolism of As are potent inhibitors of TR activity. In particular, MAsIII, an intermediate in the metabolic pathway, is an especially potent inhibitor of TR. Hence, 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.},
	keywords = {apoptosis, ENZYMATIC REDUCTION, IN-VITRO METHYLATION, LIVER, MAMMALIAN SYSTEMS, MONOMETHYLARSONOUS ACID MMA(III), NF-KAPPA-B, RABBIT ERYTHROCYTES, REDOX, REGULATION, SUBSTRATE},
	isbn = {0893-228X},
	url = {<Go to ISI>://000167723600007},
	author = {Lin, S. and Del Razo, L. M. and Styblo, M. and Wang, C. Q. and Cullen, W. R. and Thomas, D. J.}
}
@article {4600,
	title = {Methylarsenicals and arsinothiols are potent inhibitors of mouse liver thioredoxin reductase},
	journal = {Chemical Research in Toxicology},
	volume = {12},
	number = {10},
	year = {1999},
	note = {ISI Document Delivery No.: 248DFTimes Cited: 114Cited Reference Count: 64},
	month = {Oct},
	pages = {924-930},
	type = {Article},
	abstract = {Thioredoxin reductase (TR, EC 1.6.4.5) was purified 5800-fold from the livers of adult male B6C3F1 mice. The estimated molecular mass of the purified protein was about 57 kDa, The activity of the purified enzyme was monitored by the NADPH-dependent reduction of 5,5{\textquoteright}-dithiobis(2-nitrobenzoic acid) (DTNB); this activity was fully inhibited by 1 mu M aurothioglucose. Arsenicals and arsinothiols, complexes of As-III-containing compounds with L-cysteine or glutathione, were tested as inhibitors of the DTNB reductase activity of the purified enzyme. Pentavalent arsenicals were much less potent inhibitors than trivalent arsenicals. Among all the arsenicals, CH3AsIII was the most potent inhibitor of TR. CH3AsIII was found to be a competitive inhibitor of the reduction of DTNB (K-i similar to 100 nM) and a noncompetitive inhibitor of the oxidation of NADPH. The inhibition of TR by CH3AsIII was time-dependent and could not be reversed by the addition of a dithiol-containing molecule, 2,3-dimercaptosuccinic acid, to the reaction mixture. The inhibition of TR by CH3AsIII required the simultaneous presence of NADPH in the reaction mixture. However, unlike other pyridine nucleotide disulfide oxidoreductases, there was no evidence that mouse liver TR was inactivated by exposure to NADPH. Treatment with CH3AsIII did not increase the NADPH oxidase activity of the purified enzyme. Thus, CH3AsIII, a putative intermediate in the pathway for the biomethylation of As, is a potent and irreversible inhibitor of an enzyme involved in the response of the cell to oxidative stress.},
	keywords = {ARSENATE REDUCTASE, CANCER-CELLS, ENDOTHELIAL-CELLS, ESCHERICHIA-COLI, GLUTATHIONE-REDUCTASE, KAPPA-B ACTIVATION, LIPOAMIDE DEHYDROGENASE, MAMMALIAN THIOREDOXIN, MULTI-ENZYME COMPLEX, RABBIT ERYTHROCYTES},
	isbn = {0893-228X},
	url = {<Go to ISI>://000083259500008},
	author = {Lin, S. and Cullen, W. R. and Thomas, D. J.}
}
@article {4139,
	title = {Comparative inhibition of yeast glutathione reductase by arsenicals and arsenothiols},
	journal = {Chemical Research in Toxicology},
	volume = {10},
	number = {1},
	year = {1997},
	note = {ISI Document Delivery No.: WD805Times Cited: 165Cited Reference Count: 30},
	month = {Jan},
	pages = {27-33},
	type = {Article},
	abstract = {Tri(gamma-glutamylcysteinylglycinyl)trithioarsenite (As-III(GS)(3)) is formed in cells and is a more potent mixed-type inhibitor of the reduction of glutathione disulfide (GSSG) by yeast glutathione (GSH) reductase than either arsenite (As-III) or GSH. The present work examines the effects of valence and complexation of arsenicals with GSH or L-cysteine (Cys) upon potency as competitive inhibitors of the reduction of GSH disulfide (GSSG) by yeast GSH reductase. Trivalent arsenicals were more potent inhibitors than their pentavalent analogs, and methylated trivalent arsenicals were more potent inhibitors than was inorganic trivalent As. Complexation of either inorganic trivalent As or methylarsonous diiodide ((CH3AsI2)-I-III) with Cys or GSH produced inhibitors of GSH reductase that were severalfold more potent than the parent arsenicals. In contrast, dimethylarsinous iodide ((CH3)(2)(AsI)-I-III) was a more potent inhibitor than its complexes with either GSH or Cys. Complexes of CH3AsIII with GSH (CH3AsIII(GS)(2)) or with Cys (CH3AsIII(Cys)(2)) were the most potent inhibitors, with K-i{\textquoteright}s of 0.009 and 0.018 mM, respectively. Inhibition of GSH reductase by arsenicals or arsenothiols was prevented by addition of meso-2,3-dimercaptosuccinic acid (DMSA) to a mixture of enzyme, GSSG, and inhibitor before addition of NADPH. DMSA added to the reaction mixture after NADPH reversed inhibition by (CH3)(2)(AsI)-I-III but had little effect on inhibition by (CH3AsI2)-I-III, CH3AsIII(GS)(2), CH3AsIII(Cys)(2), Or AS(III)(GS)(3). Partial redox inactivation of the enzyme with NADPH increased the inhibitory potency of (CH3AsI2)-I-III and (CH3)(2)(AsI)-I-III and changed the mode of inhibition for (CH3AsI2)-I-III from competitive to noncompetitive. The greater potency of methylated trivalent arsenicals and arsenothiols than of inorganic trivalent As suggests that biomethylation of As could yield species that inhibit reduction of GSSG and alter the redox status of cells.},
	keywords = {BINDING, DIMERCAPTOSUCCINIC ACID, Disulfide, MAGNETIC-RESONANCE, MICE, PHENYLDICHLOROARSINE, RABBIT ERYTHROCYTES},
	isbn = {0893-228X},
	url = {<Go to ISI>://A1997WD80500004},
	author = {Styblo, M. and Serves, S. V. and Cullen, W. R. and Thomas, D. J.}
}
