title: The urinary metabolite profile of the dietary carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine is predictive of colon DNA adducts after a low-dose exposure in humans.
abstract: Epidemiologic evidence 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 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 [(14)C]PhIP 48 to 72 hours before surgery to remove colon tumors. Urine was collected for 24 hours after dosing for metabolite analysis, and DNA was extracted from 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-N(2)-glucuronide. Metabolite levels varied significantly between the volunteers. Interindividual differences in colon DNA adducts levels were observed between each individual. The data showed that individuals with a rapid CYP1A2 phenotype and high levels of urinary N-hydroxy-PhIP-N(2)-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-N(2)-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.
authors.affiliation: Lawrence Livermore National Laboratory, Livermore, California 94550, USA. malfatti1@llnl.gov
authors.forename: Michael A
authors.initials: MA
authors.lastname: Malfatti
authors.forename: Karen H
authors.initials: KH
authors.lastname: Dingley
authors.forename: Susan
authors.initials: S
authors.lastname: Nowell-Kadlubar
authors.forename: Esther A
authors.initials: EA
authors.lastname: Ubick
authors.forename: Nisha
authors.initials: N
authors.lastname: Mulakken
authors.forename: David
authors.initials: D
authors.lastname: Nelson
authors.forename: Nicholas P
authors.initials: NP
authors.lastname: Lang
authors.forename: James S
authors.initials: JS
authors.lastname: Felton
authors.forename: Kenneth W
authors.initials: KW
authors.lastname: Turteltaub
mesh_terms: D001191:Arylamine N-Acetyltransferase / Q000502:physiology; D015239:Arylsulfotransferase / Q000502:physiology; D002273:Carcinogens / Q000378:metabolism*; D003106:Colon / Q000378:metabolism*; D019388:Cytochrome P-450 CYP1A2 / Q000502:physiology; D018736:DNA Adducts / Q000652:urine*; D014453:Glucuronosyltransferase / Q000502:physiology; D006801:Humans; D007093:Imidazoles / Q000378:metabolism*; D000099148:UGT1A1 Enzyme
chemical_list: D001191:Arylamine N-Acetyltransferase; D015239:Arylsulfotransferase; D002273:Carcinogens; D019388:Cytochrome P-450 CYP1A2; D018736:DNA Adducts; D014453:Glucuronosyltransferase; D007093:Imidazoles; D000099148:UGT1A1 Enzyme; C049584:2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine; C504573:CYP1A2 protein, human; C478900:NAT2 protein, human; C117544:SULT1A1 protein, human