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 carcinogeni c in rodents. In F344 rats PhIP induces mammary tumors in females and colon tumors in males, while IQ induces tumors principally in the live r, Zymbal gland and intestines. In CDF1 mice, IQ induces liver, lung a nd forestomach tumors. We have evaluated the dynamics of formation, re moval and inhibition of PhIP- and IQ-DNA adducts in these rodents. Aft er 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 remo val was much slower. Gavaging of male F344 rats with PhIP (0.1-1000 mu g/kg/day) for 23 days resulted in accumulation of PhIP-DNA adducts in various organs, but adducts were detectable only at 100 or 1000 mu g/ 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 indepe ndent of duration of exposure. When weanling female F344 rats were exp osed to dietary PhIP (0.01-0.04%) for 1-4 weeks, the presence of eithe r conjugated linoleic acid (CLA; 0.1-1.0%) or indole-3-carbinol (I3C; 0.1%) in the diet inhibited PhIP-DNA adduct formation (58-99%) in vari ous organs, including the mammary gland and the colon. Similarly, the inclusion of 0.075% 4-ipomeanol (IPO) in the diet of male CDF1 mice ex posed for 3 weeks to dietary IQ (0.01%) resulted in inhibition of IQ-D NA adduct formation (30-59%) in the target organs (liver, lungs, stoma ch) 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 freque ncy of administration, (2) urinary PhIP may be a good biomarker of rec ent PhIP exposure and (3) CLA, I3C and LPO are potential chemopreventi ve agents against PhIP- or IQ-induced tumors in rodents.