Genetic predisposition to cancer is the sum of the phenotypic effects of numerous polymorphic genes that have positive or negative effects on the steps of carcinogenesis. To analyze the complicated genetic events, the use of inbred strains of mice or rats is indispensable. Hepatocarcinogenesis induced by chemicals such as 3’-methyl-dimethyl-aminoazobenzene (3’-Me-DAB) in rats is one of the most extensively studied animal models. Oral administration of 3’-Me-DAB to a susceptible strain of rats induces enzyme-altered foci (EAF), i.e., preneoplastic lesions expressing phase II enzymes, and, later, hepatocellular carcinomas (HCCs) by the progression of some EAF fairly reproducibly. Considerable differences are noted in the susceptibility to chemical induction of EAF and HCC among rat strains, but the basis of such differences is controversial. We have established an inbred strain, DRH, which shows strong resistance to 3’-Me-DAB, by selective inbreeding of carcinogen-resistant progeny starting from the “susceptible” closed colony of Donryu rats. By genetic analysis of the (DRH x F344)F2 rats fed 3’-Me-DAB, two quantitative trait loci, Drh1 and Drh2, which are responsible for DRH resistance, were mapped on rat chromosomes 1 and 4. Both QTL affected the EAF number and size, but the effect of Drh1 was limited to the preneoplastic stage. To further elucidate the function of Drh1, a speed congenic DRH.F344-Drh1 strain, i.e., DRH rats bearing the Drh1 chromosomal segment derived from F344, chromosomal segment derived from F344, was generated. The number of EAF and apoptotic liver cells in the DRH.F344-Drh1 given 3’-Me-DAB for 8 weeks was equivalent to that in F344 and far higher than that in DRH rats. A single injection of lead nitrogen, a liver mitogen, induced DNA synthesis in the resting liver cells of F344 and DRH.F344-Drh1, whereas, in the DRH liver, it induced massive apoptosis. This observation indicates that the role of the resistant Drh1 allele is to induce apoptosis in liver cells newly recruited to the cell cycle and, probably, to eliminate the initiated cells in the very early stage of carcinogenesis.
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