title: Biochemical alterations elicited in rat liver microsomes by oxidation and reduction products of chloroform metabolism.
abstract: The feasibility of an oxygen-independent mechanism of chloroform bioactivation was indicated by the covalent binding to lipid and protein occurring in anaerobic incubations of CHCl3 and microsomes in the presence of NADPH. Under these conditions, the loss of cytochrome P-450 and the inhibition of related monoxygenases were also observed. The chloroform anoxic biotransformation was negligible in uninduced microsomes and seemed to be catalyzed mainly by phenobarbital-inducible P-450 isozymes. Biotransformation could also be supported by NADH as the source of reducing equivalents. Anaerobic metabolism of chloroform led to decreased levels of the main PB-induced P-450 isozymes even at low CHCl3 concentration and did not affect benzo[a]pyrene hydroxylase activity. These effects were not decreased by thiolic compounds. The oxidation products of chloroform caused a general impairment of the monoxygenase system, probably related to the formation of protein aggregates with very high molecular weight. In the presence of physiological concentrations of GSH, the targets of aerobically-produced metabolites were lipids and, to a smaller extent, P-450. At low CHCl3 concentrations and/or in the presence of GSH the most changes to microsomal structures seemed to be produced by the reductively-formed intermediates.
mesh_terms: D000818:Animals; D002725:Chloroform / Q000378:metabolism* / Q000633:toxicity; D003577:Cytochrome P-450 Enzyme System / Q000032:analysis; D005978:Glutathione / Q000494:pharmacology; D007527:Isoenzymes / Q000032:analysis; D050356:Lipid Metabolism; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects* / Q000378:metabolism; D010084:Oxidation-Reduction; D010105:Oxygenases / Q000032:analysis; D011485:Protein Binding; D051381:Rats; D011919:Rats, Inbred Strains
chemical_list: D007527:Isoenzymes; D002725:Chloroform; D003577:Cytochrome P-450 Enzyme System; D010105:Oxygenases; D005978:Glutathione