Unique Properties of Hepatocarcinogenesis-Resistant DRH Rat Hepatocytes Linked or Not Linked to theDrh1Locus on Rat Chromosome 1

Abstract

Hepatocarcinogenesis-resistant DRH rats exhibit few and small preneoplastic hepatocytic lesions during hepatocarcinogenesis, of which traits have been assigned to two major chromosomal regions,Drh1andDrh2. In this study, hepatocytes from DRH.F344-Drh1, a congenic strain in which theDrh1chromosomal region was replaced with that of F344 rats, were compared to hepatocytes from Donryu (original strain), DRH, and F344 rats. Although DRH hepatocytes exhibited low proliferation and p38 dephosphorylation after lead nitrate (LN) treatment despite cytokine and Cox2 activation, DRH.F344-Drh1hepatocytes exhibited high responses, as did Donryu and F344 hepatocytes. Moreover, although DRH hepatocytes were resistant to hepatotoxins, DRH.F344-Drh1hepatocytes were as sensitive to hepatotoxins as Donryu and F344 hepatocytes. However, DRH.F344-Drh1hepatocytes like DRH hepatocytes proliferated at lower ratesin vitroand contained smaller nuclei than Donryu and F344 hepatocytes. Thus, low responses to LN and resistance to hepatotoxins in DRH hepatocytes were linked to theDrh1locus, while low proliferationin vitroand small nuclear size were not linked to theDrh1locus.