The effects of 1-nitropyrene, 2-amino-1-methyl-6-phenylimidazo[4,5– b]pyridine and 7,12-dimethylbenz[ a]anthracene on 8-hydroxy-2′-deoxyguanosine levels in the rat mammary gland and modulation by dietary 1,4-phenylenebis(methylene)selenocyanate

• Published in: Cancer letters Vol. 151; no. 1; pp. 7 - 13
• Main Authors: El-Bayoumy, Karam, Chae, Young-Heum, Rosa, José G, Williams, LeeAnn K, Desai, Dhimant, Amin, Shantu, Fiala, Emerich
• Format: Journal Article
• Language: English
• Published: Shannon Elsevier Ireland Ltd 03.04.2000; Elsevier
• Subjects: 9,10-Dimethyl-1,2-benzanthracene - toxicity; Animals; Anticarcinogenic Agents - administration & dosage; Anticarcinogenic Agents - pharmacology; Biological and medical sciences; Carcinogenesis, carcinogens and anticarcinogens; Carcinogens - toxicity; Chemical agents; Deoxyguanosine - analogs & derivatives; Deoxyguanosine - metabolism; Diet; DNA - drug effects; DNA - metabolism; Female; Foods and miscellaneous; Heterocyclic amines; Imidazoles - toxicity; Mammary Glands, Animal - drug effects; Mammary Glands, Animal - metabolism; Medical sciences; Nitroaromatics; Organoselenium Compounds - administration & dosage; Organoselenium Compounds - pharmacology; Oxidative damage; Polycyclic aromatic hydrocarbons; Pyrenes - toxicity; Rats; Rats, Inbred Strains; Selenium; Tumors; Heterocyclic amines; Selenium; Polycyclic aromatic hydrocarbons; Nitroaromatics; Oxidative damage; Nitro compound; Rat; Rodentia; Biological marker; Pyrene derivatives; Supplemented diet; Anticarcinogen; Polycyclic aromatic compound; Feeding; Pyridine derivatives; Selenium Cyanates; Carcinogen; Vertebrata; Mammalia; Amine; Deoxyguanosine; Corn oil; Animal; DNA; Mammary gland; Heterocyclic compound
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/S0304-3835(99)00391-2

Humans are exposed to 2-amino-1-methyl-6-phenylimidazo[4,5– b]pyridine (PhIP) and 1-nitropyrene (1-NP) via several environmental sources and both are known mammary carcinogens in rodents, with the former being more potent (K. El-Bayoumy, Y.-H. Chae, P. Upadhyaya, A. Rivenson, K. Kurtzke, B. Reddy, S.S. Hecht, Comparative tumorigenicity of benzo[ a]pyrene, 1-nitropyrene, and 2-amino-1-methyl-6-phenylimidazo[4,5– b]pyridine administered by gavage to female CD rats, Carcinogenesis 16 (1995) 431–434). Following their metabolic activation, both carcinogens are known to bind covalently to DNA. However, it remains to be determined whether these carcinogens can also induce DNA-base oxidation. Our goal was to determine the effects of PhIP and 1-NP on the levels of 8-hydroxy-2′-deoxyguanosine (8-OHdG; a marker of oxidative DNA damage) in rat mammary glands and to evaluate the effect of the chemopreventive agent 1,4-phenylenebis(methylene)selenocyanate ( p-XSC) as an inhibitor of such damage. As an established potent mammary carcinogen, the synthetic 7,12-dimethylbenz[ a]anthracene (DMBA) was included in this study. Female CD rats were fed a high-fat AIN-76A diet (23.5% corn oil) supplemented with p-XSC (10 ppm as selenium) or unsupplemented control diet for 1 week. At 50 days of age, each rat (12 rats/group) was gavaged with either PhIP (22 mg (100 μmol) per rat) or 1-NP (20 mg (80 μmol) per rat) in trioctanoin (0.5 ml), DMBA (5 mg (20 μmol) per rat] in olive oil (0.2 ml), or the corresponding vehicle. Rats were sacrificed 6 and 24 h after carcinogen treatment (six rats per time point). Mammary fat pads were excised and DNA was isolated and enzymatically hydrolyzed. The hydrolysates were analyzed for 8-OHdG using HPLC with EC detection. PhIP significantly increased the levels of 8-OHdG by 83% after 6 h ( P<0.05), but the increase (47%) at the 24 h point was not significant. p-XSC alone had no effect on the levels of 8-OHdG. However, the elevation of 8-OHdG caused by PhIP at 6 h was significantly inhibited by p-XSC to levels similar to those measured in rats treated with the vehicle only ( P<0.05). p-XSC had no effect on PhIP-induced 8-OHdG at 24 h. 1-NP had no effect on the levels of 8-OHdG at either time point. Levels of 8-OHdG were increased by 22% 6 h after DMBA administration and, significantly, rose to 84% at 24 h ( P<0.01); at either time point, this elevation was not inhibited by p-XSC. Although the mechanisms remain to be determined, to our knowledge, this is the first report demonstrating that PhIP and DMBA are capable of enhancing 8-OHdG levels in the rat mammary tissue in vivo.