Mouse liver microsomal metabolism of chloral hydrate, trichloroacetic acid, and trichloroethanol leading to induction of lipid peroxidation via a free radical mechanism.
Metabolism of chloral hydrate (CH) by male B6C3F1 mouse liver microsomes (control-microsomes) generated free radical intermediates that resulted in endogenous lipid peroxidation, forming malondialdehyde (MDA), formaldehyde (FA), acetaldehyde (ACT), acetone, and propionaldehyde. Because MDA, FA, and ACT are tumorigens, endogenous formation of lipid peroxidation products via a free radical mechanism may be responsible for hepatocellular tumorigenicity of CH to the B6C3F1 mice. Trichloroacetic acid (TCA) and trichloroethanol (TCE), the primary metabolites of CH, also generated free radicals and induced lipid peroxidation. Lipid peroxidation from TCA equaled that induced by CH, whereas that from TCE was 3- to 4-fold lower, suggesting that metabolism of CH to TCA may be the predominant pathway leading to lipid peroxidation. Metabolism of CH, TCA, and TCE by liver microsomes of mice pretreated with pyrazole (pyrazole-microsomes) yielded lipid peroxidation products at a level 2- to 3-fold higher than those from liver microsomes of untreated mice. In addition, CH-induced lipid peroxidation catalyzed by control-microsomes and pyrazole-microsomes was reduced significantly by 2,4-dichloro-6-phenylphenoxyethylamine, a general cytochrome P450 inhibitor. Thus, our study suggests that cytochrome P450 is the enzyme catalyzing the metabolic activation of CH and its metabolites (TCA and TCE) leading to lipid peroxidation, and that CYP2E1 may be the major isozyme responsible. This latter conclusion was supported by results using human lymphoblastoid cells expressing cytochrome P4502E1, which metabolized CH to reactants inducing mutations, whereas the parental cell line was inactive.
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National Center for Toxicological Research, University of Memphis, USA.
Wong
T Y
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Lloyd
R V
RV
Heinze
T M
TM
Shelton
S
S
Casciano
D
D
Kadlubar
F F
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Fu
P P
PP
D000493:Allopurinol / Q000494:pharmacology; D000818:Animals; D002384:Catalysis; D002460:Cell Line; D002697:Chloral Hydrate / Q000378:metabolism*; D005023:Ethylene Chlorohydrin / Q000031:analogs & derivatives* / Q000378:metabolism; D005609:Free Radicals; D008401:Gas Chromatography-Mass Spectrometry; D006735:Horseradish Peroxidase / Q000378:metabolism; D006801:Humans; D015227:Lipid Peroxidation; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism*; D009243:NAD / Q000494:pharmacology; D009249:NADP / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D011720:Pyrazoles / Q000378:metabolism; D014238:Trichloroacetic Acid / Q000378:metabolism*; D014969:Xanthine Oxidase / Q000494:pharmacology
D005609:Free Radicals; D011720:Pyrazoles; D009243:NAD; C031280:pyrazole; D002697:Chloral Hydrate; D009249:NADP; D014238:Trichloroacetic Acid; D000493:Allopurinol; D005023:Ethylene Chlorohydrin; C005849:2,2,2-trichloroethanol; D006735:Horseradish Peroxidase; D011451:Prostaglandin-Endoperoxide Synthases; D014969:Xanthine Oxidase