Cytochrome P-448 and the activation of toxic chemicals and carcinogens

Abstract

The metabolic activation of carcinogens and some toxic chemicals appears to involve oxygenation in conformationally hindered positions in the chemical molecules. Oxygenation of xenobiotics in hindered positions is effected by cytochrome P-448 (LM4) but not by cytochrome P-450 (LM2). Substrate-interaction spectra show that cytochrome P-448 has an active site with a conformation different from that of cytochrome P-450. Induction of cytochrome P-448, as specifically measured by ethoxyresorufin O-deethylase activity, occurs in rat liver, kidney and lung after administration of the carcinogens, 3-methylcholanthrene, Aroclor 1254, 2-anthramine, safrole, 7,12-dimethylbenz[a]anthracene, MNNG and 2-acetamidofluorene. The doubtful carcinogens, saccharin, DDT and aldrin, resulted in no significant induction. The drugs paracetamol, antipyrine, imipramine and rifampicin resulted in diminished enzyme activity, indicating the absence of any induction of cytochrome P-448. In studies with the matched pairs of carcinogens and non-carcinogens, benzo[a]pyrene and benzo[e]pyrene, and 1,2,5,6-dibenzanthracene and anthracene, only the carcinogenic analogue resulted in induction of cytochrome P-448. With alpha- and beta-naphthylamine, both resulted in marked induction of cytochrome P-448 in liver, kidney and lung, indicating that both isomers might be carcinogenic.