| Abstract
| - Studies were undertaken to determine the formation of benzylic−DNA adducts in ratsadministered 7,12-dimethylbenz[a]anthracene (DMBA) and its meso-region metabolites bysubcutaneous injection. Here, we show that 7-hydroxymethyl-12-methylbenz[a]anthracene (7-HMBA) and 7-sulfoxymethyl-12-methylbenz[a]anthracene (7-SMBA) gave rise to some benzylic−DNA adducts indistinguishable from adducts formed from DMBA. Adducts were analyzedby butanol enrichment-mediated 32P-postlabeling assay. Female Sprague−Dawley rats givena combined dose of 420 μmol DMBA/kg b. wt resulted in two major and up to nine minor adductsin the subcutaneous tissue, with chromatographic resemblance to benzylic−DNA adductsprepared in vitro. Subcutaneous administration of 7-HMBA, 7-SMBA, and 7-methyl-12-hydroxymethylbenz[a]anthracene (12-HMBA) (210, 42, and 210 μmol/kg b. wt, respectively)each resulted in one major and several minor benzylic−DNA adducts. From cochromatographywith reference adducts, it was concluded that the benzylic DNA adduct 4, derived from theparent compound, comigrates with the major adduct from 7-HMBA and 7-SMBA, whereasadducts 2 and 3 comigrate with adducts resulting from 12-HMBA and 7-methyl-12-sulfooxymethylbenz[a]anthracene, respectively. These data suggest that 7-sulfooxymethyl- and 12-sulfooxymethy derivatives produce distinct adducts. Several major and minor diol epoxide-related DNA adducts were also detected. The diol epoxide− and benzylic−DNA adducts werefound in a 2:1 ratio. The oral, intraperitoneal, and intramammiliary treatments with DMBAshowed no detectable benzylic adducts in the liver and mammary glands 24 h after the lasttreatment, although the adduct formation was clearly evident with SMBA and/or HMBAtreatments, suggesting that hydroxylation of DMBA to form HMBA may be the rate-limitingstep for the meso-methyl substitution pathway. The present study clearly demonstrates the invivo formation of benzylic−DNA adducts from DMBA. The data also reveal the involvementof the 12-methyl group of DMBA in adduct formation.
|
