||In liver cancer, aflatoxin B1 is a potent carcinogen and drug resistance is a major obstruction in chemotherapy. Certain p53 mutations may enhance drug resistance in cancer cells. This study examined aflatoxin B1-induced p53 mutations and the impact of cytosine methylation in this process and investigated whether two common p53 mutants (R248Q and R273C) in liver cancer would increase drug resistance. The p53 template was treated with aflatoxin B1 in vitro. Cytosine methylation enhances mutation at CpG sites, but no mutation at the aflatoxin B1 related hot spot at codon 249 was detected in vitro. Stable cell lines expressing the two p53 mutants (R248Q and R273C) were established by transfecting the p53-null Hep3B cells with mutant p53 expression vectors and the effect of the anti-cancer drugs, doxorubicin and taxol on the p53 mutant expressing cells were examined. The cells expressing the p53 mutant, R248Q, but not R273C, displayed cross-resistance to both drugs. Moreover, both the expression and the activity of the multiple drug resistance gene product, P-glycoprotein, were elevated in the p53 mutant R248Q expressing cells. Reduced uptake of doxorubicin was also observed in the R248Q expressing cells. These results suggest that expression of the p53 mutant, R248Q, in the liver cancer cells may enhance their drug resistance and that up-regulation of the P-glycoprotein activity may contribute to this protective effect.