Suicide inactivation of rat liver cytochrome P-450 by chloramphenicol in vivo and in vitro.
Intraperitoneal administration of chloramphenicol (100 mg/kg) to phenobarbital-treated rats causes 50% inhibition of liver microsomal 7-ethoxycoumarin and 1,1,2,2 tetrachloroethane metabolism but has no effect on the level of cytochrome P-450 detectable as its carbon monoxide complex or on the NADPH-cytochrome c reductase (EC 1.6.2.4) activity. Both the endogenous NADPH oxidase activity and the enzymatic reduction of cytochrome P-450 are inhibited by chloramphenicol treatment, whereas the Km and Ks for ethoxycoumarin and the cumene hydroperoxide- or iodosobenzene-supported deethylation of ethoxycoumarin are unaffected, suggesting that impaired electron transport to cytochrome P-450 may be the cause of the loss of enzymatic activity. Administration of [14C]chloramphenicol (100 mg/kg) leads to the covalent binding of 0.7 nmole of metabolite(s) per nanomole of the major cytochrome P-450 isozyme. Alkaline hydrolysis of a cytochrome P-450 fraction obtained by chromatography of solubilized 14C-labeled microsomes on octylamino-Sepharose releases oxalic acid and chloramphenicol oxamic acid, whereas enzymatic digestion releases N-epsilon-chloramphenicol oxamyl lysine in addition. These data obtained with radiolabeled chloramphenicol suggest that the same metabolic pathways which lead to the inactivation of cytochrome P-450 in vitro are also operative in vivo.
D015660:7-Alkoxycoumarin O-Dealkylase; D000818:Animals; D001555:Benzene Derivatives / Q000494:pharmacology; D002701:Chloramphenicol / Q000494:pharmacology*; D003374:Coumarins / Q000378:metabolism; D065607:Cytochrome P-450 Enzyme Inhibitors; D007463:Iodobenzoates / Q000494:pharmacology; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology*; D009247:NADH, NADPH Oxidoreductases / Q000378:metabolism; D019255:NADPH Oxidases; D010105:Oxygenases / Q000378:metabolism; D010634:Phenobarbital / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains
D001555:Benzene Derivatives; D003374:Coumarins; D065607:Cytochrome P-450 Enzyme Inhibitors; D007463:Iodobenzoates; C008154:2-iodosobenzoic acid; C017299:7-ethoxycoumarin; D002701:Chloramphenicol; D010105:Oxygenases; D015660:7-Alkoxycoumarin O-Dealkylase; D009247:NADH, NADPH Oxidoreductases; D019255:NADPH Oxidases; C007164:cumene hydroperoxide; D010634:Phenobarbital