Renal and hepatic toxicity of trichloroethylene and its glutathione-derived metabolites in rats and mice: sex-, species-, and tissue-dependent differences.
Acute cytotoxicity (lactate dehydrogenase release) of trichloroethylene (TRI), S-(1,2-dichlorovinyl)glutathione (DCVG), and S-(1,2-dichlorovinyl)-L-cysteine (DCVC) in freshly isolated renal cortical cells and hepatocytes from male and female rats was evaluated to test the hypothesis that the assay provides a valid indicator of sex- and tissue-dependent differences in sensitivity to TRI and its metabolites. We then determined mitochondrial toxicity (inhibition of state-3 and/or stimulation of state-4 respiration) in renal cortical and hepatic mitochondria from male and female rats and mice to assess sex-, tissue-, and species-dependent susceptibility. TRI was moderately cytotoxic in renal cells from male rats but was nontoxic in renal cells from female rats or hepatocytes from male or female rats. Acute cytotoxicity of both DCVG and DCVC was greater in renal cells from male rats than in renal cells from female rats. Although DCVC does not target the liver in vivo, it was a very potent hepatotoxicant in vitro. Mitochondrial toxicity in kidney and liver showed similar patterns, with mitochondria from male rats being more sensitive than mitochondria from female rats; order of potency was DCVC > DCVG >> TRI. State-3 respiration in mitochondria from mice was also inhibited, but the patterns and relative sensitivities differed from those in mitochondria from rats. Renal and hepatic mitochondria from mice were less sensitive than corresponding mitochondria from rats and renal mitochondria from female mice were significantly more sensitive than renal mitochondria from male mice. Thus, many of the species-, sex-, and tissue-dependent differences in toxicity observed in vivo are also observed in vitro.
Department of Pharmacology, Wayne State University School of Medicine, 540 East Canfield Ave., Detroit, MI 48201, USA. l.h.lash@wayne.edu
L H
LH
Lash
W
W
Qian
D A
DA
Putt
S E
SE
Hueni
A A
AA
Elfarra
R J
RJ
Krause
J C
JC
Parker
D000818:Animals; D004305:Dose-Response Relationship, Drug; D005260:Female; D005978:Glutathione / Q000378:metabolism*; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008928:Mitochondria / Q000187:drug effects; D009928:Organ Specificity; D051381:Rats; D011916:Rats, Inbred F344; D012737:Sex Factors; D013045:Species Specificity; D014241:Trichloroethylene / Q000378:metabolism / Q000633:toxicity*
D014241:Trichloroethylene; D007770:L-Lactate Dehydrogenase; D005978:Glutathione