Comparative mouse skin tumorigenicity and induction of Ha-ras mutations by bay region diol epoxides of 5-methylchrysene and 5,6- dimethylchrysene

We compared the tumor-initiating activities toward mouse skin of twostructurally related polycyclic aromatic hydrocarbon diol epoxides: racemicanti-1,2,3,4-tetrahydro-5,6-dimethylchrysene-1,2-diol-3,4- epoxide(5,6-diMeCDE) and racemic anti-1,2,3,4-tetrahydro-5-methylchrysene-1,2-diol-3,4-epoxide (5-MeCDE). Tumors induced by these diolepoxides were analysed for mutations in the Ha-ras gene. 5,6- diMeCDE isderived from the non-planar parent compound 5,6- dimethylchrysene, andreacts to approximately equal extents with dA and dG in DNA, whereas5-MeCDE is derived from a nearly planar parent compound, 5-methylchrysene,and reacts mainly with dG in DNA. 5,6- diMeCDE, at initiating doses of 33,100 or 400 nmol per mouse, induced 1.2, 2.2 and 6.2 skin tumors per mouse,respectively. It was significantly less tumorigenic than 5-MeCDE whichinduced 3.1, 7.5 and 9.1 skin tumors per mouse at the same doses. Tumorsinduced by 5,6- diMeCDE had a large number of CAA-->CTA mutations incodon 61 of the Ha- ras gene: 50, 55 and 75% of the tumors analysed hadthis mutation at the 33, 100 and 400 nmol doses. No mutations were found incodons 12 and 13 in the tumors induced by 5,6-diMeCDE. In contrast,CAA-->CTA mutations in codon 61 were rarely seen in tumors induced by5-MeCDE. At the highest dose of 5-MeCDE, 20% of the tumors analysed hadmutations at G of codons 12 and 13. The results of this comparative studysupport the hypothesis that mutations in the Ha-ras gene in mouse skintumors induced by PAH diol epoxides occur as a result of their directreaction with the gene. However, pathways other than the commonly observedHa- ras codon 61 mutations are clearly important in mouse skintumorigenesis by these diol epoxides.