Relationship of PhIP metabolism and DNA binding to cancer susceptibility Free

CN04-03

>Epidemiologic evidence from numerous studies indicates that exposure to heterocyclic amines in the diet is an important risk factor for the development of colon cancer. Well-done cooked meats contain significant levels of heterocyclic amines, which have been shown to cause cancer at multiple sites in laboratory animals. To better understand the mechanisms of heterocyclic amine bioactivation in humans, the most mass abundant heterocyclic amine, 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 48 to 72 hours prior to surgery for removal of colon tumors. Urine was collected for 24 hours after dosing for metabolite analysis, and DNA was extracted from biopsied colon tissue and analyzed by accelerator mass spectrometry for DNA adducts. All 10 subjects were phenotyped for cytochrome P4501A2 (CYP1A2), N-acetyltransferase 2, and sulfotransferase 1A1 enzyme activity. Twelve PhIP metabolites were detected in the urine samples. The most abundant metabolite in all volunteers was N-hydroxy-PhIP-N²-glucuronide. Not surprisingly, metabolite levels varied significantly between the volunteers. Interindividual differences in colon DNA adducts levels were observed between each individual. The data clearly showed that individuals with a rapid CYP1A2 phenotype and high levels of urinary N-hydroxy-PhIP-N²-glucuronide had the lowest level of colon PhIP-DNA adducts. This suggests that glucuronidation plays a significant role in detoxifying N-hydroxy-PhIP. The levels of urinary N-hydroxy-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. (Cancer Res 2006; 66(21): 10541-7).
 (Work supported by National Cancer Institute grants CA55861, CA55751, CA58697; Environmental Protection Agency grant R825280; and U.S. Army grant MM4559FLB and RR13461. This work was done under the auspices of the U.S. Department of Energy by Lawrence Livermore National Laboratory under contract no. W-7405- ENG-48.)