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Metabolism and DNA binding of 5,6-dimethylchrysene in mouse skin.

Abstract
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)
AuthorsB Misra, S Amin, S S Hecht
JournalChemical research in toxicology (Chem Res Toxicol) Vol. 5 Issue 2 Pg. 242-7 ( 1992) ISSN: 0893-228X [Print] United States
PMID1643254 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • Aroclors
  • Carcinogens
  • Chrysenes
  • Chlorodiphenyl (54% Chlorine)
  • 5,6-dimethylchrysene
  • DNA
Topics
  • Animals
  • Aroclors (pharmacology)
  • Biotransformation
  • Carcinogens (metabolism, toxicity)
  • Chlorodiphenyl (54% Chlorine)
  • Chromatography, High Pressure Liquid
  • Chrysenes (chemistry, metabolism, toxicity)
  • DNA (metabolism)
  • Female
  • Male
  • Mice
  • Rats
  • Rats, Inbred F344
  • Skin (drug effects, metabolism)
  • Spectrophotometry, Ultraviolet

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