Tissue distribution of DNA adducts in rats treated by intramammillary injection with dibenzo[a,l]pyrene, 7,12-dimethylbenz[a]anthracene and benzo[a]pyrene.
Dibenzo[a,l]pyrene (DBP) has recently emerged as a potent environmental carcinogen having greater carcinogenicity in the rat mammary epithelial glands than 7,12-dimethylbenz[a]anthracene (DMBA), previously considered to be the most potent mammary carcinogen and benzo[a]pyrene (BP), a ubiquitous environmental carcinogen. Previous studies on the tumor-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 mammary glands than DMBA; BP was a weak mammary carcinogen in these animals. The present study was designed to investigate if the significantly increased mammary carcinogenicity of DBP over DMBA and BP was related to increased DNA adduction at the target site. Female Sprague-Dawley rats were treated by intramammillary injection with an equimolar dose of 0.25 micromol/gland of DBP, DMBA, and BP at the 3rd, 4th and 5th mammary glands on both sides. 32P-Postlabeling analysis of mammary epithelial DNA of rats treated with DBP produced two major (nos. 3 and 6) and 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-treated 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, respectively. Tissue distribution of DNA adducts in non-target organs following DBP treatment showed similar adduct pattern as found in the mammary epithelial 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 tissues were similar to that found in mammary epithelial cells, however, significant quantitative differences were found; BP-DNA adducts were undetectable in the pancreas and bladder. Quantitation of adduct radioactivity showed a 15- to 60-fold lower DBP-DNA adduction in these tissues than the levels found in the mammary tissue; similarly 5-20 and 30-100 times lower DNA adduction was found following treatment with DMBA and BP, respectively. The significantly increased binding of DBP to the mammary epithelial DNA over BP and DMBA is in concordance with its known higher mutagenicity and tumorigenicity.
Arif
J M
JM
Preventive Medicine and Environmental Health, University of Kentucky Medical Center, Lexington 40536, USA.
Smith
W A
WA
Gupta
R C
RC
D015127:9,10-Dimethyl-1,2-benzanthracene / Q000031:analogs & derivatives / Q000378:metabolism / Q000633:toxicity*; D000818:Animals; D001564:Benzo(a)pyrene / Q000378:metabolism / Q000633:toxicity*; D001580:Benzopyrenes / Q000378:metabolism / Q000633:toxicity*; D002273:Carcinogens / Q000378:metabolism / Q000633:toxicity*; D004247:DNA / Q000378:metabolism; D018736:DNA Adducts / Q000378:metabolism*; D005260:Female; D008321:Mammary Glands, Animal / Q000187:drug effects* / Q000378:metabolism; D009153:Mutagens / Q000378:metabolism / Q000633:toxicity; D010761:Phosphorus Radioisotopes / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution; D014407:Tumor Cells, Cultured
C059444:7,12-dimethylbenz(a)anthracene-DNA adduct; D001580:Benzopyrenes; D002273:Carcinogens; D018736:DNA Adducts; D009153:Mutagens; D010761:Phosphorus Radioisotopes; C056612:benzo(a)pyrene-DNA adduct; D001564:Benzo(a)pyrene; D015127:9,10-Dimethyl-1,2-benzanthracene; D004247:DNA; C041517:dibenzo(a,l)pyrene