Altered expression of hepatic carcinogen metabolizing enzymes with liver injury in HBV transgenic mouse lineages expressing various amounts of hepatitis B surface antigen.

Abstract

The objective of this work was to evaluate the possible modulation of carcinogen metabolizing enzymes in relation to chronic infection by hepatitis B virus (HBV). This was to test whether enzyme level is altered in association with HBV gene expression per se or only when that expression was associated with an induction of liver injury. For this purpose, we studied four different HBV transgenic mouse lineages (23.3, 45.2, 50.4 and 107.5) that express the transgene encoding for the large envelope protein (HBsAg) at different levels. These lineages exhibit an associated liver injury which progresses with age and is positively correlated with the degree of accumulation of HBsAg in the hepatocytes. The modulation of levels of cytochrome P450 (1a, 2a-5, 2b, 2c, 3A4 and 2E1) and glutathione S-transferases (GST alpha and pi) involved in carcinogen metabolism was examined by immunohistochemistry in these lineages. While we observed an increase in staining intensity of P450s 1-a and 2a-5 in lineages expressing cytopathic amounts of HBsAg (lineages 50.4 and 45.2), we only observed minor changes or no changes at all for the other lineages (23.3 and 107.5). Staining with antibodies to cytosolic pi class GST demonstrated an increase in older mice, although no major alterations were observed for GST alpha. These results suggest that liver cell injury induced by accumulation of HBV antigens can result in the induction of some carcinogen metabolizing enzymes and this may be one mechanism of chemical-viral interaction in hepatocarcinogenesis.