The mutagenicity of 9-hydroxyellipticine and its induction of cytochrome P-448 activity in rat liver microsomes.
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.
D000470:Alkaloids / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D003513:Cycloheximide / Q000494:pharmacology; D019388:Cytochrome P-450 CYP1A2; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D003580:Cytochromes / Q000235:genetics*; D003609:Dactinomycin / Q000494:pharmacology; D004611:Ellipticines / Q000494:pharmacology*; D004790:Enzyme Induction; D007700:Kinetics; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism*; D006899:Mixed Function Oxygenases / Q000378:metabolism; D009152:Mutagenicity Tests; D009153:Mutagens; D009154:Mutation; D051381:Rats; D011919:Rats, Inbred Strains
D000470:Alkaloids; D000970:Antineoplastic Agents; D003580:Cytochromes; D004611:Ellipticines; D009153:Mutagens; D003609:Dactinomycin; D003577:Cytochrome P-450 Enzyme System; D003513:Cycloheximide; C008009:9-hydroxyellipticine; D006899:Mixed Function Oxygenases; C017170:Cyp1a2 protein, rat; D019388:Cytochrome P-450 CYP1A2