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.

Influence of mouse liver stored vitamin A on the induction of mutations (Ames tests) and SCE of bone marrow cells by aflatoxin B1, benzo(a)pyrene, or cyclophosphamide

“…For instance, retinol strongly inhibited the genotoxicity of the precarcinogens AFB and cyclophosphamide (CPP) but not those of dimethylbenz(a)anthracene (DMBA) or benzo(a)pyrene (BP) in the Ames test and in SCE and chromosomal aberraton studies Qin et al, 19851. Since the former and the latter two carcinogens are believed to be activated by different microsomal cytochrome P-450 isoenzymes [Bartsch et al, 1980;Ioannides et al, 1984;Weibel et al, 19801, we further proposed that retinoids may inhibit only certain forms of cytochrome P-450 Qin et al, 19851. Experiments to examine the influence of retinoids on carcinogen-induced genotoxicity as mentioned above were conducted either in bacteria or in mammalian cells in vitro, with an activation system of S9 mix and free purified retinoids. In vitro test systems cannot accurately reproduce the enormous complexicity of the living animals.…”

Interlaboratory comparison of microsomal ethoxyresorufin and pentoxyresorufin O-dealkylation determinations: standardization of assay conditions

“…In the past 10 years, increased numbers of specific isozyme forms of this cytochrome P450 system were identified (Nebert et al 1989). Quantitative and qualitative characterization, of the various isozymes of the cytochrome P-450 superfamily by genetic code, gene location, immunological properties, spectral characteristics and substrate selective metabolism is considered an important aspect of toxicological and pharmacological studies (Bostick et al 1981;Ioannides et al 1984;Burke et al 1985;McDanell et al 1987;Yang and Yoo 1988;Nebert et al 1989). Direct measurement of the O-dealkylation activities of the substrates ER and PR has become a sensitive and highly selective characteristic for induction of cytochrome P-450 isozymes IA1 by 3-methylcholanthrene (3-MC) and IIB 1 by phenobarbital (PB) Mayer 1974, 1975;Burke et al 1977;Lubet et al 1985).…”

Liver Microsomal Mixed-Function Oxidases in Response to Dietary Whole Egg Protein Levels in Rats.

“…Cytochromes P-448, a distinct family of cytochromes induced typically by 3 methylcholanthrene, direct the metabolism of chemical carcinogens towards the formation of reactive intermediates (36), and similarly, the cytochromes P-450 induced by ethanol, preferentially catalyze the activation of nitrosamines and some aromatic amines (37,38). In contrast, cytochromes P-450 induced by PB exhibit primarily a deactivating role, leading also to the ultimate detoxication of chemical carcinogens (36).…”

“…In contrast, cytochromes P-450 induced by PB exhibit primarily a deactivating role, leading also to the ultimate detoxication of chemical carcinogens (36). Therefore, it is important to retain a dietary condition to be able to evoke the maximum detoxication ability of the liver microsomal MFO system to cope with the various situations that induce the MFO system.…”