The mutagenicity of 9-hydroxyellipticine and its induction of cytochrome P-448 activity in rat liver microsomes

Abstract

Administration of a single dose of the inhibitor of the hepatic mixed function oxidases, 9-hydroxyellipticine (9-OHE), resulted in a marked increase in the cytochrome P-448 catalysed activities of ethoxyresorufin O-deethylase, biphenyl 2-hydroxylase and activation of benzo[a]pyrene to mutagens. In contrast there was no effect on the cytochrome P-450 catalysed benzphetamine N-demethylase activity. The inductive effect was prevented by simultaneous administration of the protein synthesis inhibitors cycloheximide and actinomycin D. It is concluded that 9-OHE may also act as an inducer of the hepatic microsomal mixed function oxidases, selectively inducing the synthesis of cytochrome P-448. Therefore, 9-OHE, like other inhibitors of this enzyme system, exhibits a biphasic effect, its inhibitory phase being followed by one of enzyme induction. 9-OHE was a direct mutagen in the Salmonella typhimurium strains TA 98 and TA 100.