Document Detail


Mouse liver microsomal metabolism of chloral hydrate, trichloroacetic acid, and trichloroethanol leading to induction of lipid peroxidation via a free radical mechanism.
MedLine Citation:
PMID:  8825194     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Y C Ni; T Y Wong; R V Lloyd; T M Heinze; S Shelton; D Casciano; F F Kadlubar; P P Fu
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Publication Detail:
Type:  Journal Article; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Drug metabolism and disposition: the biological fate of chemicals     Volume:  24     ISSN:  0090-9556     ISO Abbreviation:  Drug Metab. Dispos.     Publication Date:  1996 Jan 
Date Detail:
Created Date:  1996-12-30     Completed Date:  1996-12-30     Revised Date:  2007-11-15    
Medline Journal Info:
Nlm Unique ID:  9421550     Medline TA:  Drug Metab Dispos     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  81-90     Citation Subset:  IM    
Affiliation:
National Center for Toxicological Research, University of Memphis, USA.
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MeSH Terms
Descriptor/Qualifier:
Allopurinol / pharmacology
Animals
Catalysis
Cell Line
Chloral Hydrate / metabolism*
Ethylene Chlorohydrin / analogs & derivatives*,  metabolism
Free Radicals
Gas Chromatography-Mass Spectrometry
Horseradish Peroxidase / metabolism
Humans
Lipid Peroxidation*
Male
Mice
Microsomes, Liver / drug effects,  metabolism*
NAD / pharmacology
NADP / pharmacology
Prostaglandin-Endoperoxide Synthases / metabolism
Pyrazoles / metabolism
Trichloroacetic Acid / metabolism*
Xanthine Oxidase / pharmacology
Chemical
Reg. No./Substance:
0/Free Radicals; 0/Pyrazoles; 107-07-3/Ethylene Chlorohydrin; 115-20-8/2,2,2-trichloroethanol; 288-13-1/pyrazole; 302-17-0/Chloral Hydrate; 315-30-0/Allopurinol; 53-59-8/NADP; 53-84-9/NAD; 76-03-9/Trichloroacetic Acid; EC 1.11.1.-/Horseradish Peroxidase; EC 1.14.99.1/Prostaglandin-Endoperoxide Synthases; EC 1.17.3.2/Xanthine Oxidase

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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