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 'resista nce to cytotoxicity' paradigm for chemically induced hepatocarcinogene sis in rats and mice to liver neoplasia in wild English sole (Pleurone ctes vetulus). Sole resident at polycyclic aromatic hydrocarbon (PAH)- contaminated sites, such as the Duwamish Waterway in Puget Sound, Wash ington, exhibit high prevalences of hepatic neoplasms and precursor le sions related to the histogenesis of neoplasms. Previous immunohistoch emical studies ill English sole show a consistent reduction of CYP1A e xpression, localized with a pc,polyclonal antibody to Atlantic cod CYP 1A, in hepatic neoplasms and most preneoplastic foci of cellular alter ation. The present study utilized immunohistochemical localization and quantitation of CYP1A expression by image analysis, linked with quant itation of hydrophobic DNA adducts by the P-32-postlabeling method, in hepatocellular neoplasms as compared to matched samples of adjacent n on-neoplastic liver tissue from the same fish. All fish were from the Duwamish Waterway in Seattle, Washington. In the eight neoplasms asses sed (four hepatocellular adenomas, four hepatocellular carcinomas), th ere was a significant and nearly parallel reduction in DNA adduct conc entrations (56-90%) and levels of CYP1A expression (3-99%) as compared to the adjacent non-neoplastic liver tissue. These findings are consi stent with the hypothesis that neoplastic hepatocytes in English sole possess a 'resistant' phenotype in which there is a reduced capacity f or CYP1A-mediated activation of genotoxic PAHs to their toxic and carc inogenic intermediates, and a consequent reduction in the formation of covalent, hydrophobic DNA adducts front these reactive intermediates. Published by Elsevier Science Ltd.