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Comparison of Drug-metabolizing Activities in the Livers of Carcinogen-sensitive Parent Rats and Carcinogen-resistant Descendants

Department of Biochemistry, Institute for Cancer Research, Osaka University Medical School, 1-1-50, Fukushima, Fukushima-ku, Osaka 553, Japan

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-448 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 activiites 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.

¹ To whom requests for reprints should be addressed.

Received 3/13/85. Revised 7/19/85. Accepted 8/14/85.