Selective inhibition by chloramphenicol of cytochrome P-450 isozymes in rat lung and liver involved in the hydroxylation of n-hexane.
Treatment of rats with chloramphenicol causes a dose-dependent and regioselective inhibition of the metabolism of the organic solvent n-hexane in both liver and lung microsomes. A dose of chloramphenicol of 100 mg kg-1 administered i.v. or i.p. results in more than 50% inhibition of 2-hexanol formation catalyzed by microsomes from both organs, but causes no inhibition of 1-hexanol formation. The effects of chloramphenicol on 3-hexanol formation are somewhat organ-specific. In the liver 3-hexanol formation is inhibited to almost the same extent as 2-hexanol formation, whereas in the lung the inhibition of the formation of 3-hexanol is markedly less. Phenobarbital induces n-hexane metabolism in the liver but not the lung, but decreases the inhibitory potency of chloramphenicol toward both organs. In vitro chloramphenicol causes both reversible and irreversible inhibition of 2-hexanol formation in control lung microsomes. The irreversible inhibition is accompanied by the covalent binding of metabolites of chloramphenicol to the lung microsomes. The covalent binding is completely inhibited by antibodies to the major phenobarbital-induced isozyme of rat liver cytochrome P-450. These antibodies also cause more than 90% inhibition of 2-hexanol formation by lung microsomes. The results suggest that chloramphenicol acts as a selective suicide substrate of a constitutive isozyme of rat lung cytochrome P-450 involved in the 2-hydroxylation of n-hexane.
D000818:Animals; D002701:Chloramphenicol / Q000378:metabolism / Q000494:pharmacology*; D065607:Cytochrome P-450 Enzyme Inhibitors; D006586:Hexanes / Q000378:metabolism*; D006900:Hydroxylation; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000037:antagonists & inhibitors*; D008099:Liver / Q000201:enzymology*; D008168:Lung / Q000201:enzymology*; D008297:Male; D008861:Microsomes / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains
D065607:Cytochrome P-450 Enzyme Inhibitors; D006586:Hexanes; D007527:Isoenzymes; C026385:n-hexane; D002701:Chloramphenicol