One of the most significant sources of environmental exposures to carcinogens is through the diet. Epidemiologic evidence indicates that exposure to heterocyclic amines (HAs) in the diet is an important risk factor for the development of colon cancer. Well-done cooked meats contain significant levels of HAs which have been shown to cause cancer in laboratory animals. To better understand the mechanisms of HA bioactivation and potential tumor induction in humans, the most mass abundant HA, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), was used to assess the relationship between PhIP metabolism and DNA adduct formation. Ten human volunteers where administered a dietary relevant dose of 14C-PhIP (70-84 μg) 48-72 h prior to surgery to remove colon tumors. Urine was collected for 24 h after dosing for metabolite analysis, and DNA was extracted from colon tissue and analyzed by accelerator mass spectrometry for DNA adducts. All ten subjects were also phenotyped for CYP1A2, NAT2, and SULT1A1 enzyme activity. Twelve radioactive peaks associated with PhIP were detected in the urine samples. The most abundant metabolite in all ten volunteers was identified as N-OH-PhIP-N2-glucuronide. Variation in the levels of metabolites between volunteers was observed. Colon DNA adducts were detected in all ten volunteers. Interindividual differences were evident in the levels of DNA adducts between each individual. Analysis of the data showed that individuals with high levels of urinary N-OH-PhIP-N2-glucuronide, and that were categorized as having a rapid CYP1A2 phenotype had the lowest level of colon PhIP-DNA adducts. This suggests that glucuronidation plays a significant role in detoxifying PhIP. Statistical analyses showed that levels of urinary N-OH-PhIP-N2-glucuronide were negatively correlated to colon DNA adduct levels. Although it is difficult to make definite conclusions from a small data set, the results from this pilot study have encouraged further investigations using a much larger study group. This work was performed under the auspices of the U.S. DOE by LLNL under contract #W-7405-ENG-48 and supported by NCI grants CA55861, CA55751, CA58697, EPA grant R825280, U.S. Army grant MM4559FLB and RR13461.
[Proc Amer Assoc Cancer Res, Volume 47, 2006]