We compared the
tumor-initiating activities toward mouse skin of two structurally related
polycyclic aromatic hydrocarbon diol
epoxides: racemic anti-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 diol
epoxides were analysed for mutations in the Ha-ras gene.
5,6-diMeCDE is derived from the non-planar parent compound
5,6-dimethylchrysene, and reacts to approximately equal extents with dA and dG in
DNA, whereas
5-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 which induced 3.1, 7.5 and 9.1 skin
tumors per mouse at the same doses.
Tumors induced by
5,6-diMeCDE had a large number of CAA-->CTA mutations in
codon 61 of the Ha-ras gene: 50, 55 and 75% of the
tumors analysed had this mutation at the 33, 100 and 400 nmol doses. No mutations were found in
codons 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 by
5-MeCDE. At the highest dose of
5-MeCDE, 20% of the
tumors analysed had mutations at G of
codons 12 and 13. The results of this comparative study support the hypothesis that mutations in the Ha-ras gene in mouse skin
tumors induced by PAH diol
epoxides occur as a result of their direct reaction with the gene. However, pathways other than the commonly observed Ha-ras
codon 61 mutations are clearly important in mouse skin
tumorigenesis by these diol
epoxides.