Inhibition of cytochrome P-448 mixed function oxidase activity following administration of 9-hydroxyellipticine to rats

Abstract

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.