Comparative Metabolic Activation in Mouse Skin of the Weak Carcinogen 6-Methylchrysene and the Strong Carcinogen 5-Methylchrysene

Shantu Amin, Keith Huie, Assieh A. Melikian, Joanna M. Leszczynska, Stephen S. Hecht

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We compared the metabolic activation in mouse skin of the weak carcinogen 6-methylchrysene, which lacks a bay region methyl group, and the strong carcinogen 5-methylchrysene, which has a bay region methyl group. Metabolites of 6-methylchrysene were prepared using liver homogenates and were identified by their spectral properties and by comparison to synthetic standards as dihydrodiols, hydroxymethyl derivatives, and phenols; their relative levels of formation in liver homogenates from rats and mice were dependent on inducer pretreatment. In mouse skin in vivo, the major metabolite of 6-methylchrysene was trans-1,2-dihydro-1,2-dihydroxy-6-methylchry-sene (6-MeC-1,2-diol), the precursor to a bay region dihydrodiol epoxide. Its concentration was greater than that of trans-1,2-dihydro-1,2-dihydroxy-5-methylchrysene (5-MeC-1,2-diol) formed in mouse skin from 5-methylchrysene. Since 5-MeC-1,2-diol has been identified as a major proximate carcinogen of 5-methylchrysene, the further metabolism and tumorigenicity of 5-MeC-1,2-diol and 6-MeC-1,2-diol were compared. Both dihydrodiols were converted to 1,2,3,4-tetrads and to 1,2-dihydroxy metabolites to similar extents in mouse skin. However, 5-MeC-1,2-diol was significantly more active than was 6-MeC-1,2-diol as a tumor initiator on mouse skin. The formation of DNA adducts in mouse skin from 5-methylchrysene and 6-methylchrysene was compared. Both hydrocarbons gave qualitatively similar adduct patterns, but the formation of dihydrodiol epoxide type adducts was V20 as great from 6-methylchrysene as from 5-methylchrysene. The results of this study indicate that the weak tumorigenicity of 6-methylchrysene compared to that of 5-methylchrysene is not due to differing rates of formation or further metabolism of their 1,2-dihydrodk>ls but is a likely consequence of the lower activity of 1,2-dihydroxy-3,4-epoxy-1,2,3,4-tetrahydro-6-methylchrysene compared to 1,2-dihydroxy-3,4-epoxy-1,2,3,4-tetrahydro-5-methylchrysene; the unique structural feature of the latter is the presence of a methyl group and an epoxide ring in the same bay region.

Original languageEnglish (US)
Pages (from-to)6406-6412
Number of pages7
JournalCancer Research
StatePublished - Dec 1 1985

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research


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