Hepatitis B virus-induced liver injury and altered expression of carcinogen metabolising enzymes: the role of the HBx protein

Hepatitis B virus (HBV) and aflatoxins are major risk factors for hepatocel lular carcinoma (HCC) exhibiting a synergistic interaction in the developme nt of this disease. The molecular mechanisms of this interaction remain to be elucidated but an altered carcinogen metabolism in the presence of hepat itis-induced liver injury is one hypothesis. The availability of biomarkers of aflatoxin exposure and metabolism permits this hypothesis to be examine d in human populations whilst animal models, such as HBV transgenic mice pe rmit parallel studies in an experimental setting. The hepatitis B virus X p rotein (HBx) is suspected to play a role in the hepatocarcinogenic process by virtue of its capacity to transactivate oncogenes and several other cell ular genes via cis-acting elements. In previous studies in HBV transgenic m ice expressing the HE surface antigen and X genes we observed a marked indu ction of specific cytochrome P450s (CYP) (Kirby et al., 1994a). In the curr ent study we investigated the status of CYP, glutathione S-transferases (GS T) and antioxidant enzymes in mice carrying only the X gene under the contr ol of the alpha-1 antitrypsin regulatory elements (ATX mice). Livers of ATX mice showed no major pathological alterations compared to age-matched non- transgenic control mice. Immunohistochemical staining for CYP1A, 2A5 and GS T expression and determination of related enzymatic activities (7-ethoxyres orufin O-deethylation, 7-methoxyresorufin O-deethylation, coumarin 7-hydrox ylation and GST activities) revealed no differences between control and ATX mice. In addition, no differences in antioxidant enzymes were observed. Ov erall, these results support the conclusion that HBx expression alone is in sufficient to induce transactivation of CYP and GST genes or to alter the a ntioxidant system and that the induction in other HBV models is a result of inflammatory injury in the liver, a feature absent in ATX mice. These data are compared to biomarker studies of enzyme activities in aflatoxin-expose d human populations with and without HBV infection. (C) 1998 Elsevier Scien ce Ireland Ltd. All rights reserved.