INCREASED SENSITIVITY TO THE HEPATOCARCINOGEN DIETHYLNITROSAMINE IN TRANSGENIC MICE CARRYING THE HEPATITIS-B VIRUS X-GENE

The role of the hepatitis B virus (HBV) X protein in liver tumorigenes is is unresolved. Transgenic mice harboring the X gene (nt 1376-1840 u nder the control of the human alpha-1-antitrypsin regulatory elements) (ATX mice) display only minor histopathologic alterations of the live r. To determine if ATX mice are more susceptible to the effects of hep atocarcinogens, 12- to 15-d-old male ATX and control littermate mice w ere injected with a single dose (2 mu g/g body weight) of diethylnitro samine (DEN). The animals were killed 6-10 mo after exposure and were analyzed for histological changes in the liver. One hundred percent of the DEN-treated ATX mice developed abnormal liver lesions. When their liver tissues were compared by stereological analysis with those of n on-transgenic animals, the ATX mice had a relative twofold increase in the total number of focal lesions and a twofold increase in the incid ence of hepatocellular carcinoma. Elevated levels of X protein and p53 protein were not detected in carcinogen-induced nodules or tumors. Th ese results are consistent with a model in which the expression of the HBV X protein potentiates the induction of DEN-mediated liver disease . (C) 1996 Wiley-Liss, Inc.