Effect of mitogenic or regenerative cell proliferation on lacz mutant frequency in the liver of Muta (TM) Mice treated with 5,9-dimethyldibenzo[c,g]carbazole

The purpose of this work was to investigate the impact of cell proliferatio n on liver mutagenesis. The genotoxic hepatocarcinogen 5,9-dimethyldibenzo[ c,g]carbazole (DMDBC) was administered to lacZ transgenic Muta(TM)Mice at a nonhepatotoxic dose of 10 mg/kg, which induces only a slight increase in t he liver lacZ mutant frequency (RIF), To determine if cell proliferation st imuli enhanced DMDBC mutagenicity, MF was analyzed in mice first receiving DMDBC 10 mg/kg, then similar to 2 weeks later, either carbon tetrachloride (CCl4, a cytotoxic agent inducing regenerative cell proliferation) or pheno barbital (PB, a mitogenic agent inducing direct hyperplasia). In preliminar y studies, the extent of cell proliferation induced by CCl4, PB and DMDBC w as determined in non-transgenic CD2F1 mice by means of 5-bromadeoxyuridine labeling. The labeling index was significantly increased after CCl4 and PB, while no change was detected with DMDBC. MF was then determined in Muta(TM )Mice 28 days after initial DMDBC treatment. No increase in MF was detected in mice receiving CCl4 or PB alone. A 2- to 3-fold increase in MF was dete cted in mice treated with 10 mg/kg DMDBC alone. In contrast, RIF was marked ly increased in mice receiving DMDBC followed by proliferative treatment (1 5-fold with CCl4 and 25-fold with PB), These results demonstrate that expre ssion of DMDBC-induced mutations in mouse liver largely depends on the indu ction of cell proliferation (by a cytotoxic or mitogenic stimulus) and illu strate that Muta(TM)Mouse is a valuable tool to investigate the early event s of liver carcinogenesis.