Genetic resistance to chemical carcinogen-induced preneoplastic hepatic lesions in DRH strain rats

DRH strain rats were established by inbreeding a closed colony of Donryu ra ts continuously fed the chemical hepatocarcinogen 3'-methyl-4-dimethylamino azobenzene for over 10 years. They are highly resistant to chemical inducti on of liver cancer and preneoplastic lesions. We studied the genetic basis of DRH resistance to preneoplastic lesions by analyzing 108 (F344 x DRH)F-2 male rats fed 3'-methyl-4-dimethylaminoazobenzene for 7 weeks, Five parame ters of preneoplastic liver lesions were selected for quantitative analysis : (a) number of glutathione S-transferase placental form-positive foci per unit area of liver section; (b) percentage area occupied by the foci; (c) a verage size of foci; (d) glutathione S-transferase placental form mRNA leve l; and (e) gamma-glutamyltranspeptidase mRNA level, Furthermore, O-6-methyl guanine DNA methyltransferase and mannose 6-phosphatase/insulin-like growth factor 2 receptor mRNA levels were quantified. Composite interval mapping analysis showed that there were two remarkably significant clusters of quan titative trait loci affecting preneoplastic liver lesions on chromosomes 1 and 4. These clusters were designated collectively as Drh1 and Drh2, respec tively. The functions of the recessive DRH allele of Drh1 and the semidomin ant DRH allele of Drh2 were to suppress the phenotypes of precancerous lesi ons. Each cluster showed two to three subpeaks in linkage likelihood plots, suggesting the presence of several closely linked quantitative trait loci affecting preneoplastic lesions. Possible candidate genes at each locus wil l be discussed. Expression of O-6-methylguanine DNA methyltransferase and m annose 6-phosphatase/insulin-like growth factor 2 receptor did not affect D RH resistance to hepatocarcinogenesis, although they were polymorphic betwe en DRH and F344 rats.