Dissociation of cytochrome P-450 inactivation and induction.
Polycyclic aromatic hydrocarbons bind to a cytosolic receptor that translocates into the nucleus and induces the synthesis of mRNA for a subset of cytochrome P-450 isozymes. The failure to detect a "phenobarbital" receptor, however, suggests that the induction of P-450b/e, the isozymes induced by phenobarbital, is mediated by a less direct mechanism. One attractive alternative is that a receptor exists for an endogenous substance that is specifically turned over by the trace amounts of P-450b/e present in uninduced liver. Changes in the concentration of this substance caused by agents that inhibit P-450b/e would then trigger the induction response. We report here that suppressing the catalytic activities of P-450b/e for prolonged periods with 1-aminobenzotriazole, a mechanism-based irreversible inhibitor, neither induces P-450b/e nor interferes with induction of these isozymes at the level of transcription by phenobarbital. The results argue against mechanisms for the induction of P-450b/e keyed to the effective catalytic availability of these isozymes.
D000818:Animals; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D004790:Enzyme Induction / Q000187:drug effects; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology; D010634:Phenobarbital / Q000494:pharmacology; D014176:Protein Biosynthesis / Q000187:drug effects; D012333:RNA, Messenger / Q000187:drug effects; D051381:Rats; D011919:Rats, Inbred Strains; D014230:Triazoles / Q000494:pharmacology
D065607:Cytochrome P-450 Enzyme Inhibitors; D007527:Isoenzymes; D012333:RNA, Messenger; D014230:Triazoles; C033020:1-aminobenzotriazole; D003577:Cytochrome P-450 Enzyme System; D010634:Phenobarbital