Selective inhibition of the safrole-induced mixed-function oxidase activities by 9-hydroxyellipticine.
Intraperitoneal administration of 9-hydroxyellipticine, a specific cytochrome P-448 inhibitor, inhibited 3-methylcholanthrene-induced cytochrome P-448 activity (ethoxyresorufin O-deethylase, biphenyl 2-hydroxylase) and formation of the safrole carbene ligand complex with this cytochrome, but did not inhibit phenobarbital-induced cytochrome P-450 activity (ethyl-morphine N-demethylase) or formation of the safrole carbene ligand complex with this cytochrome. Biphenyl displaced the 9-hydroxyellipticine ligand from cytochrome P-448 leading to increased free cytochrome, but with no corresponding increase in mixed-function oxidase activity when biphenyl was used as substrate. It is concluded that following dissociation of the ligand complex, 9-hydroxyellipticine, which also exhibits type I binding, competes with biphenyl for the substrate binding site. Administration of 9-hydroxyellipticine to safrole-pretreated rats inhibited the cytochrome P-448-catalysed activity, but had no effect on the cytochrome P-450-catalysed activity. These results indicate that safrole induces a mixture of cytochromes P-450 and P-448 rather than a single novel haemo-protein. The type I substrate biphenyl displaced both the safrole carbene and the 9-hydroxyellipticine ligands from cytochrome P-448 resulting in increased free cytochrome. Displacement of the safrole carbene ligand was accompanied by increased mixed-function oxidase activity but, in contrast, displacement of the 9-hydroxyellipticine ligand resulted in no increase in mixed-function oxidase activity.
D000470:Alkaloids / Q000494:pharmacology*; D000818:Animals; D001665:Binding Sites; D001713:Biphenyl Compounds / Q000494:pharmacology; D019388:Cytochrome P-450 CYP1A2; D003580:Cytochromes / Q000037:antagonists & inhibitors; D004149:Dioxoles / Q000378:metabolism*; D004611:Ellipticines / Q000494:pharmacology*; D004790:Enzyme Induction / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology*; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors*; D010088:Oxidoreductases / Q000037:antagonists & inhibitors*; D051381:Rats; D011919:Rats, Inbred Strains; D012451:Safrole / Q000378:metabolism*
D000470:Alkaloids; D001713:Biphenyl Compounds; D019388:Cytochrome P-450 CYP1A2; D003580:Cytochromes; D004149:Dioxoles; D004611:Ellipticines; D006899:Mixed Function Oxygenases; D010088:Oxidoreductases; D012451:Safrole; C010574:biphenyl; C008009:9-hydroxyellipticine; C017170:Cyp1a2 protein, rat