Isozyme selectivity of the inhibition of rat liver cytochromes P-450 by chloramphenicol in vivo.
The isozyme-selectivity of chloramphenicol as an inhibitor of rat liver cytochromes P-450 has been investigated. Untreated rats and rats treated with the inducers phenobarbital, beta-naphthoflavone, pregnenolone 16 alpha-carbonitrile, and clofibrate have been injected intraperitoneally with chloramphenicol, and inhibition of specific cytochrome P-450 isozymes has been assessed by monitoring the metabolism of warfarin, testosterone, isosafrole, or lauric acid in subsequently prepared hepatic microsomal preparations. Of eight major cytochrome P-450 isozymes which could be monitored in this fashion, three were inhibited by more than 50% by a dose of chloramphenicol of 300 mg/kg, whereas no evidence of inhibition of the remaining isozymes was obtained. P-450PB-C, an isozyme which is present in significant amounts in untreated rats and which is induced approximately 2-fold by phenobarbital, was the most susceptible cytochrome P-450 to inhibition by chloramphenicol both in vivo and in vitro. P-450PB-B, the major phenobarbital-inducible isozyme, and P-450UT-A, a male-specific testosterone 2 alpha- and 16 alpha-hydroxylase, were intermediate in their susceptibility to chloramphenicol. In contrast, the major isozymes induced by beta-naphthoflavone, pregnenolone 16 alpha-carbonitrile, and clofibrate, as well as a constitutive testosterone 7 alpha-hydroxylase, were not inhibited by chloramphenicol.
D000818:Animals; D001571:Benzoflavones / Q000494:pharmacology; D002701:Chloramphenicol / Q000494:pharmacology*; D002994:Clofibrate / Q000494:pharmacology; D065607:Cytochrome P-450 Enzyme Inhibitors; D007527:Isoenzymes / Q000037:antagonists & inhibitors*; D007850:Lauric Acids / Q000378:metabolism; D008099:Liver / Q000201:enzymology*; D008297:Male; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors; D010634:Phenobarbital / Q000494:pharmacology; D011285:Pregnenolone Carbonitrile / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D012451:Safrole / Q000378:metabolism; D039181:Steroid 16-alpha-Hydroxylase; D013379:Substrate Specificity; D013739:Testosterone / Q000378:metabolism; D014859:Warfarin / Q000378:metabolism; D019324:beta-Naphthoflavone
D001571:Benzoflavones; D065607:Cytochrome P-450 Enzyme Inhibitors; D007527:Isoenzymes; D007850:Lauric Acids; C030358:lauric acid; D011285:Pregnenolone Carbonitrile; D013739:Testosterone; D014859:Warfarin; D019324:beta-Naphthoflavone; D002701:Chloramphenicol; D006899:Mixed Function Oxygenases; D039181:Steroid 16-alpha-Hydroxylase; D002994:Clofibrate; D012451:Safrole; C015959:isosafrole; D010634:Phenobarbital