Benzo[a]pyrene‐induced mutagenesis of p53 hot‐spot codons 248 and 249 in human hepatocytes

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Abstract
Human tobacco‐related cancers show a high frequency of G‐to‐T transversions in several mutation hot‐spot regions of the p53 tumor suppressor gene, probably the result of specific mutagens in tobacco smoke, most notably benzo[a]pyrene. To gain insight into the mechanism of formation of these G‐to‐T transversions in tobacco‐associated carcinogenesis, we studied the mutagenesis of p53 codons 247–250 by benzo[a]pyrene in human hepatocellular carcinoma cells by restriction fragment length polymorphism‐polymerase chain reaction genotypic analysis. Benzo[a]pyrene preferentially induced G‐to‐T transversion in the second and third positions of codon 248 and C‐to‐A transversion in the first position of codon 248. However, benzo[a]pyrene did not induce base‐pair changes in codon 249, which is a mutational hot‐spot in aflatoxin‐related hepatocardno‐genesis, in which predominantly G‐to‐T transversion in the third psition of codon 249 is observed. The benzo[a]pyrene‐induced G‐to‐T transversion in the middle position of codon 248, in which arginine is changed into leucine, is frequently observed in tumors of the lung. The other two benzo[a]pyrene‐induced base‐pair changes in codon 248, namely the C‐to‐A transversion in the first position and G‐to‐T transversion in the third position, do not lead to a change in the amino‐acid composition of the p53 protein. These mutations are silent and therefore are not selected in tumors. It follows that benzo[a]pyrene‐induced mutability on the DNA level in p53 codons 247–250 correlates well with the type of mutation found in tumors of the lung. Therefore, our results support the hypothesis that benzo[a]pyrene is the etiological agent in tobacco‐related Cancers.