PT  - JOURNAL ARTICLE
AU  - J Halpert
AU  - B Näslund
AU  - I Betnér
TI  - Suicide inactivation of rat liver cytochrome P-450 by chloramphenicol in vivo and in vitro.
DP  - 1983 Mar 01
TA  - Molecular Pharmacology
PG  - 445--452
VI  - 23
IP  - 2
4099  - http://molpharm.aspetjournals.org/content/23/2/445.short
4100  - http://molpharm.aspetjournals.org/content/23/2/445.full
SO  - Mol Pharmacol1983 Mar 01; 23
AB  - 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.