Cytochrome P450-dependent metabolism of trichloroethylene: interindividual differences in humans.
Trichloroethylene (TRI) is an industrial solvent with a history of use in anesthesia, and is a common groundwater contaminant. Cytochrome P450 (CYP)-dependent metabolism of TRI produces chloral hydrate (CH) and is rate limiting in the ultimate production of trichloro- and/or dichloroacetic acid from TRI. Exposure of rodents to TRI results in lung and liver tumors (mice) and nephrotoxicity (rats). The toxicity is exacerbated by pretreatment of mice with CYP inducers. We report significant variability in TRI metabolism in a sample of 23 human hepatic microsomal samples and demonstrate the dependence of TRI metabolism on CYP2E1. K(m) values in this limited sample population are not normally distributed. We have correlated microsomal CH formation with the activity toward routine CYP2E1 substrates and with immunologically detectable CYP2E1 protein. Further, TRI metabolism in microsomes from lymphoblastoid cell lines expressing CYP2E1, CYP1A1, CYP1A2, or CYP3A4 indicated minimal involvement of the latter forms, with CYP2E1 catalyzing more than 60% of total microsomal TRI metabolism. These results indicate that humans are not uniform in their capacity for CYP-dependent metabolism of TRI and increased CYP2E1 activity may increase susceptibility to TRI-induced toxicity in the human.
Lipscomb
J C
JC
United States Air Force, Armstrong Laboratory, Toxicology Division, OL-AL HSC/OET, Wright-Patterson Air Force Base, Ohio 45433-7400, USA. JLipscomb@AL.WPAFB.AF.MIL
Garrett
C M
CM
Snawder
J E
JE
D000704:Analysis of Variance; D001711:Biotransformation; D015153:Blotting, Western; D002753:Chlorzoxazone / Q000378:metabolism / Q000494:pharmacology; D019392:Cytochrome P-450 CYP2E1 / Q000276:immunology / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000276:immunology / Q000378:metabolism*; D004586:Electrophoresis; D005260:Female; D006801:Humans; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism*; D018570:Risk Assessment; D012997:Solvents / Q000378:metabolism*; D013045:Species Specificity; D014241:Trichloroethylene / Q000378:metabolism* / Q000494:pharmacology
D012997:Solvents; D014241:Trichloroethylene; D003577:Cytochrome P-450 Enzyme System; D019392:Cytochrome P-450 CYP2E1; D002753:Chlorzoxazone