Expression of hepatitis B virus X protein does not alter the accumulation of spontaneous mutations in transgenic mice

Chronic infection with hepatitis B virus (HBV) is one of the major etiologi cal factors in the development of human hepatocellular carcinoma. Transgeni c mice that express the HBV X protein (HBx) have previously been shown to b e more sensitive to the effects of hepatocarcinogens, although the mechanis m for this cofactor role remains unknown. The ability of HBx to inhibit DNA repair in transiently transfected cell lines suggests one possible pathway . In the present study, primary hepatocytes isolated from transgenic mice t hat possess the HBV X gene under the control of the human alpha-1-antitryps in regulatory region (ATX mice) were found to be deficient in their ability to conduct unscheduled DNA synthesis in response to UV-induced DNA damage. In order to measure the impact of HBx expression on DNA repair in vivo, do uble-transgenic mice that express HBx and possess a bacteriophage Lambda tr ansgene were sacrificed at 30, 90, and 240 days of age. Mutation frequency was determined for high-molecutar-weight liver DNA of ATX and control mite by functional analysis of the lambda transgene. Expression of HBx did not s ignificantly increase the accumulation of spontaneous mutations. These resu lts are consistent with previous studies of HBx transgenic mice in which no effect of HBx on liver histology was apparent. This new animal model provi des a powerful system in which to investigate the in vivo cooperation betwe en HBx expression and environmental carcinogens.