Role of resistant Drh1 locus in chemical carcinogen-induced hepatocarcinogenesis in rats: analysis with a speed congenic strain.

The DRH is an inbred rat strain established by selective mating of the 3'-Me-DAB resistant progeny of closed colony Donryu rats over 20 generations. Genetic analysis shows that two semidominant QTLs, Drh1 and Drh2, are responsible for strong resistance to chemical-induced hepatocarcinogenesis in DRH strain rats. To evaluate the effect of the single Drh1 locus on various stages of liver carcinogenesis, we constructed a speed congenic strain DRH.F344-Drh1 by transferring a susceptible Drh1 allele of F344 to DRH rats by marker-assisted backcrossing. The DRH.F344-Drh1 rats had a approximately 43 cM segment of chromosome 1 bearing Drh1 but the Drh2 was of the DRH allele. After oral administration of 3'-Me-DAB for 8 weeks, DRH.F344-Drh1 had as many enzyme altered foci as F344, whereas the quantitative parameters of fibrosis, enzyme altered foci, GST-P expression and proliferation of liver cells in DRH.F344-Drh1 rats were intermediate between F344 and DRH. In the liver of carcinogen-fed DRH rats, there was intensive apoptosis as detected by TUNEL stain, but not in the liver of F344 and DRH.F344-Drh1 rats. Injection of lead nitrate (100 micromol/kgB.W) induced a wave of liver cell proliferation, as seen by BrdU uptake within a few days in F344 and DRH.F344-Drh1 rats, but not in DRH rats. Instead, there were numerous TUNEL-positive nuclei in the DRH liver after lead nitrate injection. Apparently, the hepatocytes were removed by apoptosis during transition from G0 to G1. The major role of Drh1 is effective removal of the hepatocytes newly recruited to proliferate after chemical injury. Resistance to preneoplastic lesions in DRH rats may well be based on similar mechanism.