Metabolism and DNA Binding of 5,6-Dimethylchrysene in Mouse Skin

Bijaya Misra, Shantu Amin, Stephen S. Hecht

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17 Scopus citations


5,6-Dimethylchrysene (5,6-diMeC) is a weaker tumor initiator on mouse skin than 5-methylchrysene (5-MeC). To investigate the reasons for the unexpectedly low activity of 5,6-diMeC, we have studied its metabolism and DNA binding in mouse skin, particularly with respect to metabolic activation via its anti-1,2-diol 3,4-epoxide. The metabolism of 5,6-diMeC was first examined with liver 9000g supernatant from Aroclor 1254 pretreated rats. Three major metabolites were identified as 1- or 7-hydroxy-5-(hydroxymethyl)-6-MeC, 1,2-dihydroxy-1,2-dihydro-5,6-diMeC (5,6-diMeC-1,2-diol), and 1-hydroxy-5,6-diMeC. The formation of 5,6-diMeC-1,2-diol was then assessed in mouse epidermis, following topical application of [3H]5,6- diMeC. Levels of 5,6-diMeC-1,2-diol in epidermis exceeded those of 5-MeC-1,2-diol formed from 5-MeC under similar conditions. The binding of [3H]5,6-diMeC and that of [3H]5-MeC to mouse epidermal DNA were then compared. 5,6-DiMeC-deoxyribonucleoside adducts were prepared as markers by reaction of anti- and syn-5,6-diMeC-1,2-diol 3,4-epoxide with calf thymus DNA. HPLC analysis of enzymatic hydrolysates of mouse epidermal DNA, isolated 18 h after topical treatment with [3H] 5,6-diMeC or [3H] 5-MeC, demonstrated the formation from [3H] 5,6-diMeC of two major adducts produced by reaction of its anti-1,2-diol 3,4-epoxide with deoxyguanosine and deoxyadenosine, respectively, while the major adduct formed from [3H] 5-MeC resulted from reaction with deoxyguanosine, in agreement with previous results. Total DNA binding of [3H]5-MeC as well as formation of deoxyguanosine adducts exceeded that of [3H]5,6-diMeC by 3-4-fold. The results of this study demonstrate that the metabolic activation pathway 5,6-diMeC → 5,6-diMeC-1,2-diol → anti-5,6-diMeC-1,2-diol 3,4-epoxide exists in mouse skin, as in the case of 5-MeC. The results suggest however that the conversion of 5,6-diMeC-1,2-diol to anti-5,6-diMeC-1,2-diol 3,4-epoxide in mouse skin does not occur as efficiently as the corresponding conversion of 5-MeC-1,2-diol to its anti-1,2-diol 3,4-epoxide. The results are discussed with respect to a structurally similar nonplanar compound, benzo [c] phenanthrene, which also has weak tumorigenicity on mouse skin, apparently resulting in part from inefficient metabolism of its 3,4-diol to bay region diol epoxides.

Original languageEnglish (US)
Pages (from-to)242-247
Number of pages6
JournalChemical research in toxicology
Issue number2
StatePublished - Mar 1 1992

All Science Journal Classification (ASJC) codes

  • Toxicology


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