Abstract

The DRH is an inbred rat strain established by selective mating of the 3'-Me-DAB resistant progeny of closed colony Donryu rats. Genetic analysis shows that two semi-dominant QTLs, Drh1 and Drh2, are responsible for strong resistance to chemical-induced hepatocarcinogenesis in DRH 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. After oral administration of 3'-DAB for 8 weeks, 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 μmol/kg. B. 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. The major role of Drh1 is effective removal of the hepatocytes newly recruited to proliferate after chemical injury.