DNA adducts of heterocyclic amines: formation, removal and inhibition by dietary components.
The dietary mutagens 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) are carcinogenic in rodents. In F344 rats PhIP induces mammary tumors in females and colon tumors in males, while IQ induces tumors principally in the liver, Zymbal gland and intestines. In CDF1 mice, IQ induces liver, lung and forestomach tumors. We have evaluated the dynamics of formation, removal and inhibition of PhIP- and IQ-DNA adducts in these rodents. After bolus doses (50 mg/kg, by gavage) of IQ or PhIP, both IQ- and PhIP-DNA adducts were removed rapidly from both target and nontarget organs, while after 3-4 weeks of feeding IQ or PhIP (0.01-0.04%) adduct removal was much slower. Gavaging of male F344 rats with PhIP (0.1-1000 micrograms/kg/day) for 23 days resulted in accumulation of PhIP-DNA adducts in various organs, but adducts were detectable only at 100 or 1000 micrograms/kg/day. Urinary excretion of unchanged PhIP was a constant proportion (1.6-2.1%) of the daily dose over the entire dose range and was independent of duration of exposure. When weanling female F344 rats were exposed to dietary PhIP (0.01-0.04%) for 1-4 weeks, the presence of either conjugated linoleic acid (CLA; 0.1-1.0%) or indole-3-carbinol (13C; 0.1%) in the diet inhibited PhIP-DNA adduct formation (58-99%) in various organs, including the mammary gland and the colon. Similarly, the inclusion of 0.075% 4-ipomeanol (IPO) in the diet of male CDF1 mice exposed for 3 weeks to dietary IQ (0.01%) resulted in inhibition of IQ-DNA adduct formation (30-59%) in the target organs (liver, lungs, stomach) but not in a number of other organs. It is concluded that (1) the rate of PhIP- and IQ-DNA adduct removal depends on the dose and frequency of administration, (2) urinary PhIP may be a good biomarker of recent PhIP exposure and (3) CLA, I3C and IPO are potential chemopreventive agents against PhIP- or IQ-induced tumors in rodents.
Schut
H A
HA
Department of Pathology, Medical College of Ohio, Toledo 43614, USA.
Cummings
D A
DA
Smale
M H
MH
Josyula
S
S
Friesen
M D
MD
D000588:Amines / Q000378:metabolism*; D000818:Animals; D016587:Antimutagenic Agents / Q000494:pharmacology; D002273:Carcinogens / Q000378:metabolism*; D018736:DNA Adducts / Q000096:biosynthesis*; D004260:DNA Repair; D004032:Diet; D005260:Female; D005753:Gastric Mucosa / Q000378:metabolism; D006571:Heterocyclic Compounds / Q000378:metabolism*; D007093:Imidazoles / Q000378:metabolism; D007211:Indoles / Q000378:metabolism; D019787:Linoleic Acid; D008041:Linoleic Acids / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D008321:Mammary Glands, Animal / Q000378:metabolism; D051379:Mice; D011804:Quinolines / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D013729:Terpenes / Q000378:metabolism; D014018:Tissue Distribution
D000588:Amines; D016587:Antimutagenic Agents; D002273:Carcinogens; D018736:DNA Adducts; D006571:Heterocyclic Compounds; D007093:Imidazoles; D007211:Indoles; D008041:Linoleic Acids; D011804:Quinolines; D013729:Terpenes; C029216:2-amino-3-methylimidazo(4,5-f)quinoline; C049584:2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine; D019787:Linoleic Acid; C016517:indole-3-carbinol; C001470:4-ipomeanol