title: Caffeine Cytochrome P450 1A2 Metabolic Phenotype Does Not Predict the Metabolism of Heterocyclic Aromatic Amines in Humans.
abstract: 2-Amino-1-methylimidazo[4,5-b]pyridine (PhIP) and 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) are carcinogenic heterocyclic aromatic amines (HAAs) formed in well-done cooked meats. Chemicals that induce cytochrome P450 (P450) 1A2, a major enzyme involved in the bioactivation of HAAs, also form in cooked meat. Therefore, well-done cooked meat may pose an increase in cancer risk because it contains both inducers of P450 1A2 and procarcinogenic HAAs. We examined the influence of components in meat to modulate P450 1A2 activity and the metabolism of PhIP and MeIQx in volunteers during a 4 week feeding study of well-done cooked beef. The mean P450 1A2 activity, assessed by caffeine metabolic phenotyping, ranged from 6.3 to 7.1 before the feeding study commenced and from 9.6 to 10.4 during the meat feeding period: the difference in means was significant (P < 0.001). Unaltered PhIP, MeIQx, and their P450 1A2 metabolites, N(2)-(β-1-glucosiduronyl)-2-(hydroxyamino)-1-methyl-6-phenylimidazo[4,5-b]pyridine (HON-PhIP-N(2)-Gl); N3-(β-1-glucosiduronyl)-2-(hydroxyamino)-1-methyl-6-phenylimidazo[4,5-b]pyridine (HON-PhIP-N3-Gl); 2-amino-3-methylimidazo-[4,5-f]quinoxaline-8-carboxylic acid (IQx-8-COOH); and 2-amino-8-(hydroxymethyl)-3-methylimidazo[4,5-f]quinoxaline (8-CH2OH-IQx) were measured in urine during days 2, 14, and 28 of the meat diet. Significant correlations were observed on these days between the levels of the unaltered HAAs and their oxidized metabolites, when expressed as percent of dose ingested or as metabolic ratios. However, there was no statistically significant correlation between the caffeine P450 1A2 phenotype and any urinary HAA biomarker. Although the P450 1A2 activity varied by greater than 20-fold among the subjects, there was a large intraindividual variation of the P450 1A2 phenotype and inconsistent responses to inducers of P450 1A2. The coefficient of variation of the P450 1A2 phenotype within-individual ranged between 1 to 112% (median = 40%) during the entire course of the study. The caffeine metabolic phenotype for P450 1A2 was a poor predictor of oxidative urinary metabolites of PhIP and MeIQx and may not be a reliable measure to assess the role of HAAs in cancer risk.
authors.affiliation: †Masonic Cancer Center and Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota, 2231 Sixth Street SE, Minneapolis, Minnesota 55455, United States.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Turesky
authors.affiliation: ‡University of Hawaii Cancer Center, University of Hawaii, 701 Ilalo Street, Honolulu, Hawaii 96813, United States.
authors.forename: Kami K
authors.initials: KK
authors.lastname: White
authors.affiliation: ‡University of Hawaii Cancer Center, University of Hawaii, 701 Ilalo Street, Honolulu, Hawaii 96813, United States.
authors.forename: Lynne R
authors.initials: LR
authors.lastname: Wilkens
authors.affiliation: ‡University of Hawaii Cancer Center, University of Hawaii, 701 Ilalo Street, Honolulu, Hawaii 96813, United States.
authors.forename: Loïc
authors.initials: L
authors.lastname: Le Marchand
mesh_terms: D000588:Amines / Q000378:metabolism* / Q000652:urine; D000818:Animals; D002110:Caffeine / Q000378:metabolism; D002417:Cattle; D002851:Chromatography, High Pressure Liquid; D003296:Cooking; D019388:Cytochrome P-450 CYP1A2 / Q000032:analysis / Q000235:genetics* / Q000378:metabolism*; D004435:Eating; D005260:Female; D064368:Healthy Volunteers; D006571:Heterocyclic Compounds / Q000378:metabolism* / Q000652:urine; D057166:High-Throughput Screening Assays; D006801:Humans; D008297:Male; D008460:Meat; D010641:Phenotype
chemical_list: D000588:Amines; D006571:Heterocyclic Compounds; D002110:Caffeine; D019388:Cytochrome P-450 CYP1A2