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.
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 beta-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 microM DCVCS for 24 h exhibited morphological changes, although at least 100 microM DCVCS was required to produce marked changes. Acute cellular necrosis did not occur until 48 h with at least 200 microM 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 microM DCVCS and the extent of apoptosis was much less than that with DCVC. Mitochondrial function was maintained with DCVCS concentrations up to 100 microM, 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 microM 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.
Lash
Lawrence H
LH
Department of Pharmacology, Wayne State University School of Medicine, 540 East Canfield Ave., Detroit, MI 48201, USA. l.h.lash@wayne.edu
Putt
David A
DA
Hueni
Sarah E
SE
Krause
Renee J
RJ
Elfarra
Adnan A
AA
D017209:Apoptosis; D048429:Cell Size / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003545:Cysteine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects* / Q000502:physiology; D009336:Necrosis; D013454:Sulfoxides / Q000494:pharmacology*
D013454:Sulfoxides; C039961:S-(1,2-dichlorovinyl)cysteine; D007770:L-Lactate Dehydrogenase; D005978:Glutathione; D003545:Cysteine