Reductions in CYP1A expression and hydrophobic DNA adducts in liver neoplasms of English sole ( Pleuronectes vetulus): Further support for the ‘resistant hepatocyte’ model of hepatocarcinogenesis

Our recent studies have investigated the applicability of the ‘resistance to cytotoxicity’ paradigm for chemically induced hepatocarcinogenesis in rats and mice to liver neoplasia in wild English sole ( Pleuronectes vetulus). Sole resident at polycyclic aromatic hydrocarbon (PAH)-contaminated sites, such as the Duwamish Waterway in Puget Sound, Washington, exhibit high prevalences of hepatic neoplasms and precursor lesions related to the histogenesis of neoplasms. Previous immunohistochemical studies in English sole show a consistent reduction of CYP1A expression, localized with a polyclonal antibody to Atlantic cod CYP1A, in hepatic neoplasms and most preneoplastic foci of cellular alteration. The present study utilized immunohistochemical localization and quantitation of CYP1A expression by image analysis, linked with quantitation of hydrophobic DNA adducts by the 32P-postlabeling method, in hepatocellular neoplasms as compared to matched samples of adjacent non-neoplastic liver tissue from the same fish. All fish were from the Duwamish Waterway in Seattle, Washington. In the eight neoplasms assessed (four hepatocellular adenomas, four hepatocellular carcinomas), there was a significant and nearly parallel reduction in DNA adduct concentrations (56–90%) and levels of CYP1A expression (3–99%) as compared to the adjacent non-neoplastic liver tissue. These findings are consistent with the hypothesis that neoplastic hepatocytes in English sole possess a ‘resistant’ phenotype in which there is a reduced capacity for CYP1A-mediated activation of genotoxic PAHs to their toxic and carcinogenic intermediates, and a consequent reduction in the formation of covalent, hydrophobic DNA adducts from these reactive intermediates.