Dietary omega-3 fatty acids as potential inhibitors of carcinogenesis: effect on DNA adduct formation of 2-amino-1-methyl-6-phenylimidazo[4,5- b]pyridine (PhIP) in mice and rats

• Published in: Food and chemical toxicology 1999-04, Vol.37 (4), p.287-296
• Main Authors: Josyula, S, Schut, H.A.J
• Format: Article
• Language: English
• Subjects: 2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine; Animals; Anticarcinogenic Agents - therapeutic use; Biological and medical sciences; Body Weight - drug effects; Carcinogenesis, carcinogens and anticarcinogens; Carcinogens - metabolism; cecum; Chemoprevention; colon; diet; DNA adducts; DNA Adducts - biosynthesis; dna modification; Fatty Acids, Omega-3 - therapeutic use; Female; food mutagens; Foods and miscellaneous; heterocyclic amines; Imidazoles - metabolism; inhibition; leukocyte count; liver; long chain fatty acids; Male; Medical sciences; Mice; Mice, Inbred Strains; omega-3-fatty acids; oral administration; PhIP; polyunsaturated fatty acids; pyridines; Rats; Rats, Inbred F344; small intestine; stomach; Tumors
• ISSN: 0278-6915; 1873-6351
• DOI: 10.1016/S0278-6915(99)00018-6

The heterocyclic amine 2-amino-1-methyl-6-phenylimidazo[4,5- b]pyridine (PhIP) is carcinogenic in the CDF 1 mouse, causing lymphomas (spleen and lymph nodes) and in the F344 rat, causing mammary tumours in the female and colon tumours in the male. Dietary fish oil, a rich source of ω-3 fatty acids, exhibits chemopreventive properties in several rodent tumour models. The potential chemopreventive properties of dietary ω-3 fatty acid ethyl ester concentrate (O3C) were tested by evaluating its effects on the formation and removal of PhIP–DNA adducts. In the first experiment, a powdered AIN-76A diet containing 4.0% (w/w) O3C inhibited PhIP–DNA adduct formation in various organs of the CDF 1 mouse, but not in those of the F344 rat. In a subsequent, second experiment, groups of male CDF 1 mice were maintained for 43 days on AIN-76A diets containing the following percentages (w/w) of corn oil ethyl esters and O3C: 7.0 and 0, 5.5 and 1.5, 4.0 and 3.0, and 1.0 and 6.0, respectively. All animals received 0.04% (w/w) PhIP in the diet during weeks 3 and 4. Using 32P-postlabelling assays, PhIP–DNA adducts were analysed in various organs and white blood cells (WBC) on days 1, 8 and 15 after removal of PhIP from the diet. In the liver, O3C-containing diets inhibited adduct formation at all three time points (40.3–60.0%, 53.4–75.7% and 43.3–64.3% on days 1, 8 and 15, respectively). In the spleen, inhibition was evident only on days 8 (35.4–38.8%) and 15 (38.4–56.5%). O3C diets inhibited adduct formation in the stomach, small intestine and caecum at all three time points (except in the stomach and caecum on day 15) amounting to 18.5–31.5% decreases in the stomach, 40.0–60.3% decreases in the small intestine and 24.4–31.4% decreases in the caecum. The extent of inhibition was not related to O3C concentration. In the colon and WBC, adduct levels were independent of the type of diet. In all organs, adduct levels decreased significantly over time, with day 15 levels being 6.3–31.6% of those on day 1. Rate of adduct removal was independent of the type of diet. It is concluded that dietary O3C inhibits PhIP–DNA adduct formation in a target organ (spleen) as well as in non-target organs (liver and gastrointestinal tract) of the CDF 1 mouse, but that the rate of adduct removal is independent of the O3C content of the diet.