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. (C) 2000 Elsevier Science Ireland Ltd.
All Science Journal Classification (ASJC) codes
- Cancer Research