Modulation of hepatic and renal metabolism and toxicity of trichloroethylene and perchloroethylene by alterations in status of cytochrome P450 and glutathione.
The relative importance of metabolism of trichloroethylene (Tri) and perchloroethylene (Perc) by the cytochrome P450 (P450) and glutathione (GSH) conjugation pathways in their acute renal and hepatic toxicity was studied in isolated cells and microsomes from rat kidney and liver after various treatments to modulate P450 activity/expression or GSH status. Inhibitors of P450 stimulated GSH conjugation of Tri and, to a lesser extent, Perc, in both kidney cells and hepatocytes. Perc was a more potent, acute cytotoxic agent in isolated kidney cells than Tri but Perc-induced toxicity was less responsive than Tri-induced toxicity to modulation of P450 status. These observations are consistent with P450-dependent bioactivation being more important for Tri than for Perc. Incubation of isolated rat hepatocytes with Tri produced no acute cytotoxicity in isolated hepatocytes while Perc produced comparable cytotoxicity as in kidney cells. Modulation of P450 status in hepatocytes produced larger changes in Tri- and Perc-induced cytotoxicity than in kidney cells, with non-selective P450 inhibitors increasing toxicity. Induction of CYP2E1 with pyridine also markedly increased sensitivity of hepatocytes to Tri but had little effect on Perc-induced cytotoxicity. Increases in cellular GSH concentrations increased Tri- and Perc-induced cytotoxicity in kidney cells but not in hepatocytes, consistent with the role of GSH conjugation in Tri- and Perc-induced nephrotoxicity. In contrast, depletion of cellular GSH concentrations moderately decreased Tri- and Perc-induced cytotoxicity in kidney cells but increased cytotoxicity in hepatocytes, again pointing to the importance of different bioactivation pathways and modes of action in kidney and liver.
Lash
Lawrence H
LH
Department of Pharmacology, Wayne State University School of Medicine, Detroit, MI 48201, United States. l.h.lash@wayne.edu
Putt
David A
DA
Huang
Paul
P
Hueni
Sarah E
SE
Parker
Jean C
JC
D000818:Animals; D001711:Biotransformation / Q000187:drug effects; D002274:Carcinogens, Environmental / Q000378:metabolism / Q000633:toxicity*; D002470:Cell Survival / Q000187:drug effects; D002753:Chlorzoxazone / Q000494:pharmacology; D019392:Cytochrome P-450 CYP2E1 / Q000096:biosynthesis; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000378:metabolism*; D004050:Ditiocarb / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005978:Glutathione / Q000378:metabolism*; D022781:Hepatocytes / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D066298:In Vitro Techniques; D007672:Kidney Cortex / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D007700:Kinetics; D008297:Male; D008797:Metyrapone; D008861:Microsomes / Q000187:drug effects / Q000378:metabolism; D011335:Proadifen / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344; D013750:Tetrachloroethylene / Q000378:metabolism / Q000633:toxicity*; D014241:Trichloroethylene / Q000378:metabolism / Q000633:toxicity*
D002274:Carcinogens, Environmental; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D011725:Pyridines; D014241:Trichloroethylene; D003577:Cytochrome P-450 Enzyme System; D004050:Ditiocarb; D011335:Proadifen; D019392:Cytochrome P-450 CYP2E1; D005978:Glutathione; D002753:Chlorzoxazone; C023666:pyridine; D013750:Tetrachloroethylene; D008797:Metyrapone