Metabolism and DNA binding of 5,6-dimethylchrysene in mouse skin.
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.(ABSTRACT TRUNCATED AT 250 WORDS)
Misra
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Division of Chemical Carcinogenesis, American Health Foundation, Valhalla, New York 10595.
Amin
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Hecht
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D000818:Animals; D001140:Aroclors / Q000494:pharmacology; D001711:Biotransformation; D002273:Carcinogens / Q000378:metabolism* / Q000633:toxicity; D020111:Chlorodiphenyl (54% Chlorine); D002851:Chromatography, High Pressure Liquid; D002911:Chrysenes / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity; D004247:DNA / Q000378:metabolism*; D005260:Female; D008297:Male; D051379:Mice; D051381:Rats; D011916:Rats, Inbred F344; D012867:Skin / Q000187:drug effects / Q000378:metabolism*; D013056:Spectrophotometry, Ultraviolet
D001140:Aroclors; D002273:Carcinogens; D002911:Chrysenes; D020111:Chlorodiphenyl (54% Chlorine); C043380:5,6-dimethylchrysene; D004247:DNA