RT Journal Article SR Electronic T1 Roles of Necrosis, Apoptosis, and Mitochondrial Dysfunction in S-(1,2-Dichlorovinyl)-L-cysteine Sulfoxide-Induced Cytotoxicity in Primary Cultures of Human Renal Proximal Tubular Cells JF Journal of Pharmacology and Experimental Therapeutics JO J Pharmacol Exp Ther FD American Society for Pharmacology and Experimental Therapeutics SP 1163 OP 1172 DO 10.1124/jpet.102.046185 VO 305 IS 3 A1 Lawrence H. Lash A1 David A. Putt A1 Sarah E. Hueni A1 Renee J. Krause A1 Adnan A. Elfarra YR 2003 UL http://jpet.aspetjournals.org/content/305/3/1163.abstract AB S-(1,2-Dichlorovinyl)-l-cysteine (DCVC) is the penultimate nephrotoxic metabolite of the environmental contaminant trichloroethylene. Although metabolism of DCVC by the cysteine conjugate β-lyase is the most studied bioactivation pathway, DCVC may also be metabolized by the flavin-containing monooxygenase (FMO) to yield DCVC sulfoxide (DCVCS). Renal cellular injury induced by DCVCS was investigated in primary cultures of human proximal tubular (hPT) cells by assessment of time- and concentration-dependent effects on cellular morphology, acute cellular necrosis, apoptosis, mitochondrial function, and cellular glutathione (GSH) status. Confluent hPT cells incubated with as little as 10 μM DCVCS for 24 h exhibited morphological changes, although at least 100 μM DCVCS was required to produce marked changes. Acute cellular necrosis did not occur until 48 h with at least 200 μM DCVCS, indicating that this is a high-dose, late response. The extent of necrosis was similar to that with DCVC. In contrast, apoptosis occurred as early as 1 h with as little as 10 μM DCVCS and the extent of apoptosis was much less than that with DCVC. Mitochondrial function was maintained with DCVCS concentrations up to 100 μM, consistent with hPT cells only being competent to undergo apoptosis at early time points and relatively low concentrations. Marked depletion (>50%) of cellular GSH content was only observed with 500 μM DCVCS. These results, combined with previous studies showing protection from DCVC-induced necrosis and apoptosis by the FMO inhibitor methimazole, suggest that formation of DCVCS plays a significant role in trichloroethylene-induced renal cellular injury in hPT cells. The American Society for Pharmacology and Experimental Therapeutics