Aflatoxin‐B exposure does not lead to p53 mutations but results in enhanced liver cancer of Hupki (human p53 knock‐in) mice

Hepatocellular carcinoma (HCC) is a common human malignancy that is often associated with risk factors such as aflatoxin‐B 1 (AFB 1 ) exposure and Hepatitis‐B virus infection in developing countries. There is a strong correlation between these risk factors and mutation of the tumor‐suppressor gene p53 at codon 249. In vitro experiments have also shown that treatment of human liver cells with AFB 1 results in p53 mutations. A tumor‐promoting role for mutant p53 was demonstrated using transgenic mice models, in which HCC development was accelerated upon AFB 1 ‐exposure. However, wild‐type mice in which AFB 1 alone was used to induce liver cancers have failed to recapitulate p53 mutations, raising the possibility that mouse DNA context may not be appropriate for the generation of AFB 1 ‐induced p53 mutations. We have now tested this hypothesis using the Hupki mice (human p 53 knock‐in) in which the mouse DNA‐binding domain has been replaced by the homologous human p53 segment. Mice were followed for 80 weeks after AFB 1 injection for survival and HCC formation. Hupki mice were found to be more susceptible to AFB 1 than wild‐type mice. Moreover, only 19% of wild‐type mice developed HCCs compared to 44% in Hupki mice. However, none of the liver tumors and normal tissues from Hupki mice contained any mutations in the DNA‐binding domain of p53 . These findings suggest that the human DNA context of the p53 gene alone may not be the sole determinant of AFB 1 ‐induced mutagenesis. Furthermore, humanized p53 appears not to be as effective as murine p53 in the mouse cellular environment in preventing malignant transformation. © 2006 Wiley‐Liss, Inc.