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

✍ Scribed by Pascal Cherpillod; Paul A. Amstad

• Book ID: 102947811
• Publisher: John Wiley and Sons
• Year: 1995
• Tongue: English
• Weight: 605 KB
• Volume: 13
• Category: Article
• ISSN: 0899-1987
• DOI: 10.1002/mc.2940130104

✦ Synopsis

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[alpyrene in human hepatocellular carcinoma cells by restriction fragment length polymorphism-polymerase chain reaction genotypic analysis. Benzo[alpyrene preferentially induced G-to-T transversion in the second and third positions of codon 248 and C-to-A transversion in the first position o f codon 248. However, benzo[a]pyrene did not induce base-pair changes in codon 249, which is a mutational hot-spot in aflatoxin-related hepatocarcinogenesis, in which predominantly G-to-T transversion in the third psition o f 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 o f the lung. The other t w o 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 n o t lead t o a change i n the amino-acid composition o f the p53 protein. These mutations are silent and therefore are not selected in tumors. It follows that benzo[alpyrene-induced mutability on t h e DNA level in p53 codons 247-250 correlates well with t h e type o f mutation found i n tumors of t h e lung. Therefore, our results support the hypothesis that benzo[alpyrene is the etiological agent in tobacco-related cancers.