Enhancement of DNA binding, mutagenicity and carcinogenicity of polycyclic aromatic hydrocarbons after induction of cytochrome P-450 by ellipticines in rats and mice.
Pretreatment of rats by ellipticines enhanced the microsomal concentration of cytochrome P-450, benzo[alpha]pyrene (BP) metabolism and activation and, a smaller extent, ethoxycoumarin deethylation, but not acetanilide hydroxylation. This increased BP biotransformation was essentially due to the formation of bay-region metabolites, BP 9,10-diol, BP 7,8-diol and 9-hydroxy-BP, or to the formation of BP 7,8-diol-9,10-epoxide- and of 9-hydroxy-BP 4,5-oxide-DNA adducts. In the ellipticine series, 9-fluoroellipticine (9-FE) presents a slight inducing potency compared with the parent and 9-hydroxy molecules. Pretreatment of mice with 9-hydroxyellipticine (9-OHE) led also to an increased mutagenicity of BP and to an augmentation of skin carcinogenesis by 7,12-dimethylbenz[alpha]anthracene (DMBA). These results clearly show that 9-OHE induces the biosynthesis of cytochrome P-450 which markedly stimulates the mutagenic and carcinogenic potentialities of polycyclic aromatic hydrocarbons (PAH).
D000470:Alkaloids / Q000494:pharmacology*; D000818:Animals; D001564:Benzo(a)pyrene; D001580:Benzopyrenes / Q000378:metabolism; D003374:Coumarins / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D004247:DNA / Q000378:metabolism*; D004347:Drug Interactions; D004611:Ellipticines / Q000494:pharmacology*; D004790:Enzyme Induction; D008297:Male; D051379:Mice; D011083:Polycyclic Compounds / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains
D000470:Alkaloids; D001580:Benzopyrenes; D003374:Coumarins; D004611:Ellipticines; D011083:Polycyclic Compounds; C017299:7-ethoxycoumarin; D001564:Benzo(a)pyrene; D004247:DNA; D003577:Cytochrome P-450 Enzyme System