Increased sensitivity to the hepatocarcinogen diethylnitrosamine in transgenic mice carrying the hepatitis B virus X gene

Mol Carcinog. 1996 Apr;15(4):261-9. doi: 10.1002/(SICI)1098-2744(199604)15:4<261::AID-MC3>3.0.CO;2-J.

Abstract

The role of the hepatitis B virus (HBV) X protein in liver tumorigenesis is unresolved. Transgenic mice harboring the X gene (nt 1376-1840 under the control of the human alpha-1-antitrypsin regulatory elements) (ATX mice) display only minor histopathologic alterations of the liver. To determine if ATX mice are more susceptible to the effects of hepatocarcinogens, 12- to 15-d-old male ATX and control littermate mice were injected with a single dose (2 microgram/g body weight) of diethylnitrosamine (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 AXT mice developed abnormal liver lesions. Then their liver tissues were compared by stereological analysis with those of non-transgenic animals, the ATX mice had a relative twofold increase in the total number of focal lesion and a twofold increase in the incidence of hepatocellular carcinoma. Elevated levels of X protein and p53 protein were not detected in carcinogen-induced nodules or tumors. These results are consistent with a model in which the expression of the HBV X protein potentiates the induction of DEN-mediated liver disease.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Age Factors
  • Alkylating Agents / administration & dosage*
  • Animals
  • Carcinogens / administration & dosage*
  • DNA, Viral
  • Diethylnitrosamine / administration & dosage*
  • Dose-Response Relationship, Drug
  • Female
  • Gene Expression Regulation, Viral
  • Genes, Viral
  • Hepatitis B virus / genetics
  • Liver Neoplasms / chemically induced
  • Liver Neoplasms / genetics*
  • Liver Neoplasms, Experimental / chemically induced
  • Liver Neoplasms, Experimental / genetics*
  • Male
  • Mice
  • Mice, Transgenic
  • Trans-Activators / genetics*
  • Viral Structural Proteins / genetics

Substances

  • Alkylating Agents
  • Carcinogens
  • DNA, Viral
  • Trans-Activators
  • Viral Structural Proteins
  • hepatitis B virus X protein
  • Diethylnitrosamine