Inhibition of cytochrome P-448 mixed function oxidase activity following administration of 9-hydroxyellipticine to rats.
The in vitro inhibitor of mixed-function oxidation, 9-hydroxyellipticine, non-competitively inhibited the binding of the type II substrate, aniline, to cytochrome P-448 of hepatic microsomal preparations from rats pretreated with 3-methylcholanthrene. In contrast, 9-hydroxyellipticine did not inhibit the binding of aniline to cytochrome P-450 of hepatic microsomal preparations from rats pretreated with phenobarbitone, nor did it inhibit the binding of the type I substrate, hexobarbitone to either cytochrome P-450 or cytochrome P-448. Following the pretreatment of rats intraperitoneally with 9-hydroxyellipticine and phenobarbitone, the cytochrome P-448-specific enzyme activity, ethoxyresorufin O-deethylase, was 50% inhibited in vitro but cytochrome P-450, cytochrome P-450 reductase, and other mixed function oxidase activities were unaffected. With rats pretreated with 9-hydroxyellipticine and 3-methylcholanthrene, inhibition of ethoxyresorufin O-deethylase was 90%, and cytochrome P-450/P-448, cytochrome P-450 reductase, biphenyl 2- and 4-hydroxylase were inhibited by 30, 15, 50 and 40% respectively. It is concluded that 9-hydroxyellipticine administered in vivo markedly inhibits mixed-function oxidations which are specific to cytochrome P-448, but has no effect on cytochrome P-450-catalysed microsomal oxidation.
D000470:Alkaloids / Q000494:pharmacology*; D000814:Aniline Compounds / Q000378:metabolism; D000818:Animals; D019388:Cytochrome P-450 CYP1A2; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D003580:Cytochromes / Q000037:antagonists & inhibitors*; D004611:Ellipticines / Q000494:pharmacology*; D006591:Hexobarbital / Q000378:metabolism; D008297:Male; D008748:Methylcholanthrene / Q000494:pharmacology; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors*; D010088:Oxidoreductases / Q000037:antagonists & inhibitors*; D010634:Phenobarbital / Q000494:pharmacology; D051381:Rats
D000470:Alkaloids; D000814:Aniline Compounds; D003580:Cytochromes; D004611:Ellipticines; D008748:Methylcholanthrene; D003577:Cytochrome P-450 Enzyme System; C008009:9-hydroxyellipticine; D006591:Hexobarbital; D006899:Mixed Function Oxygenases; D010088:Oxidoreductases; C017170:Cyp1a2 protein, rat; D019388:Cytochrome P-450 CYP1A2; D010634:Phenobarbital