TISSUE DISTRIBUTION OF DNA-ADDUCTS IN RATS TREATED BY INTRAMAMMILLARYINJECTION WITH DIBENZO[A,L]PYRENE, 7,12-DIMETHYLBENZ[A]ANTHRACENE ANDBENZO[A]PYRENE

Dibenzo[a,l]pyrene (DBP) has recently emerged as a potent environmenta l carcinogen having greater carcinogenicity in the rat mammary epithel ial glands than 7,12-dimethylbenz[ a]anthracene (DMBA), previously con sidered to be the most potent mammary carcinogen and benzo[a]pyrene (B P), a ubiquitous environmental carcinogen, Previous studies on the tum or-initiating potential of DBP, DMBA, and BP demonstrated that DBP was 2.5 times more potent in inducing the tumors in mouse skin and rat ma mmary glands than DMBA; BP was a weak mammary carcinogen in these anim als, The present study was designed to investigate if the significantl y increased mammary carcinogenicity of DBP over DMBA and BP was relate d to increased DNA adduction at the target site. Female Sprague-Dawley rats were treated by intramammillary injection with an equimolar dose of 0.25 mu mol/gland of DBP, DMBA, and BP at the 3rd, 4th and 5th mam mary glands on both sides. P-32-Postlabeling analysis of mammary epith elial DNA of rats treated with DBP produced two major (nos. 3 and 6) a nd at least 5 minor adducts. DMBA treatment resulted in one major and 4 minor DNA adducts while BP produced one major and two minor adducts. Quantitation of the adduct radioactivity revealed that DNA adduction was 6- and 9-fold greater in DBP-treated animals than in BP-and DMBA-t reated animals, respectively. The adduct levels per 10(9) nucleotides in mammary epithelial cells for DBP, BP and DMBA were in the following descending order: 1828 +/- 378, 300 +/- 45 and 207 +/- 72, respective ly. Tissue distribution of DNA adducts in non-target organs following DBP treatment showed similar adduct pattern as found in the mammary ep ithelial cells except the liver, which resulted in 4 additional adduct spots; vehicle-treated tissue DNA processed in parallel did not show any detectable adducts, DMBA-and BP-DNA adduct patterns in various tis sues were similar to that found in mammary epithelial cells, however, significant quantitative differences were found; BP-DNA adducts were u ndetectable in the pancreas and bladder. Quantitation of adduct radioa ctivity showed a 15- to 60-fold lower DBP-DNA adduction in these tissu es than the levels found in the mammary tissue; similarly 5-20 and 30- 100 times lower DNA adduction was found following treatment with DMBP, and BP, respectively, The significantly increased binding of DBP to t he mammary epithelial DNA over BP and DMBA is in concordance with its known higher mutagenicity and tumorigenicily. (C) 1997 Elsevier Scienc e B.V.