Comparison of drug-metabolizing activities in the livers of carcinogen-sensitive parent rats and carcinogen-resistant descendants.
Donryu strain albino rats were maintained on a diet containing 0.06% 3'-methyl-4-dimethylaminoazobenzene (3'-Me-DAB) for nine successive generations. Some rats in the fourth to eighth generations showed marked resistance to the carcinogenic action of 3'-Me-DAB. In the liver where we found tumors, their size and number are smaller than in the corresponding original strain of rats fed on a diet containing 3'-Me-DAB. No significant differences were found in the total cytochrome P-450 contents or epoxide hydrolase activities of the livers of the resistant variant and the original strain, but the benzo(a)pyrene hydroxylase activity which is mainly attributed to cytochrome P-448 and glutathione S-transferase activity of the resistant variant were lower. The inductions of hepatic cytochrome P-488 and benzo(a)pyrene hydroxylase on administration of polychlorinated biphenyls or 3-methylcholanthrene were also lower in the resistant rats. In the mutagenicity test on Salmonella typhimurium TA 98 the liver 9000 X g supernatant fraction from 3'-Me-DAB-resistant F7 rats did not fully induce the mutagenicities of 3'-Me-DAB and several other carcinogens. Thus the resistance of F7 rats to the chemical carcinogen may be related to the lower activities of some drug-metabolizing enzymes and the poor inducibility of cytochrome P-448 in their liver, although selection of resistant rats should be continued for further generations before coming to a definite conclusion on biochemical basis of apparent resistance to 3'-Me-DAB.
D000818:Animals; D001579:Benzopyrene Hydroxylase / Q000378:metabolism; D001711:Biotransformation; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004351:Drug Resistance; D004851:Epoxide Hydrolases / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism; D008099:Liver / Q000201:enzymology* / Q000378:metabolism; D008113:Liver Neoplasms / Q000139:chemically induced*; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced*; D008748:Methylcholanthrene / Q000494:pharmacology; D008749:Methyldimethylaminoazobenzene / Q000378:metabolism* / Q000494:pharmacology; D009152:Mutagenicity Tests; D051381:Rats; D013057:Spectrum Analysis; D004124:p-Dimethylaminoazobenzene / Q000031:analogs & derivatives*
D008749:Methyldimethylaminoazobenzene; D008748:Methylcholanthrene; D003577:Cytochrome P-450 Enzyme System; D004124:p-Dimethylaminoazobenzene; D001579:Benzopyrene Hydroxylase; D005982:Glutathione Transferase; D004851:Epoxide Hydrolases