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.
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 micromol) per rat) or I-NP (20 mg (80 micromol) per rat) in trioctanoin (0.5 ml), DMBA (5 mg (20 micromol) 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. I -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.
El-Bayoumy
K
K
American Health Foundation, Valhalla, NY 10595, USA. kelbayoumy@aol.com
Chae
Y H
YH
Rosa
J G
JG
Williams
L K
LK
Desai
D
D
Amin
S
S
Fiala
E
E
D000080242:8-Hydroxy-2'-Deoxyguanosine; D015127:9,10-Dimethyl-1,2-benzanthracene / Q000633:toxicity*; D000818:Animals; D016588:Anticarcinogenic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D002273:Carcinogens / Q000633:toxicity*; D004247:DNA / Q000187:drug effects* / Q000378:metabolism; D003849:Deoxyguanosine / Q000031:analogs & derivatives* / Q000378:metabolism; D004032:Diet; D005260:Female; D007093:Imidazoles / Q000633:toxicity*; D008321:Mammary Glands, Animal / Q000187:drug effects* / Q000378:metabolism*; D016566:Organoselenium Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D011721:Pyrenes / Q000633:toxicity*; D051381:Rats; D011919:Rats, Inbred Strains
D016588:Anticarcinogenic Agents; D002273:Carcinogens; D007093:Imidazoles; D016566:Organoselenium Compounds; D011721:Pyrenes; D015127:9,10-Dimethyl-1,2-benzanthracene; C074153:1,4-phenylenebis(methylene)selenocyanate; D000080242:8-Hydroxy-2'-Deoxyguanosine; D004247:DNA; C049584:2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine; D003849:Deoxyguanosine; C032668:1-nitropyrene