title: CYP2A6 activity determined by caffeine phenotyping: association with colorectal cancer risk.
abstract: Cytochrome P450 2A6 (CYP2A6) catalyzes the metabolic activation of several procarcinogens including dietary and environmental nitrosamines, and the involvement of CYP2A6 in cancer development has been postulated. CYP2A6 phenotype was determined using caffeine as a probe drug in individuals participating in a case-control study of colorectal cancer (127 cases and 333 controls matched on age, gender, race, and geographic region). Conversion of the caffeine metabolite 1,7-dimethylxanthine (17X) to 1,7-dimethyl uric acid (17U) is catalyzed primarily by CYP2A6, and this activity can be assayed by comparison of urinary molar ratios of metabolites. Caffeine (200 mg) was administered to each participant, and a 4-5 h postadministration urine sample was collected. Urinary metabolites of caffeine were separated by high-performance liquid chromatography and quantified by comparison to authentic standards. We examined the distributions of the ratio, 17U:17X, according to subject characteristics among controls. In case-control comparisons, subjects in the medium and high tertiles of CYP2A6 activity had an increased risk of colorectal cancer compared with subjects with low activity. Odds ratios from a conditional logistic regression model for medium and high 17U:17X ratio were 2.0 (95% confidence interval, 1.1-3.7) and 2.6 (95% confidence interval, 1.5-4.5), respectively (P for trend = 0.001). CYP2A6 phenotype has not been compared previously between cancer cases and controls. We found a strong relationship between CYP2A6 activity, measured by urinary caffeine metabolite ratio, and colorectal cancer risk.
authors.affiliation: Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USA. nowellsusana@uams.edu
authors.forename: Susan
authors.initials: S
authors.lastname: Nowell
authors.forename: Carol
authors.initials: C
authors.lastname: Sweeney
authors.forename: George
authors.initials: G
authors.lastname: Hammons
authors.forename: Fred F
authors.initials: FF
authors.lastname: Kadlubar
authors.forename: Nicholas P
authors.initials: NP
authors.lastname: Lang
mesh_terms: D000328:Adult; D000368:Aged; D001189:Aryl Hydrocarbon Hydroxylases; D015415:Biomarkers / Q000652:urine; D002110:Caffeine / Q000378:metabolism*; D016022:Case-Control Studies; D000697:Central Nervous System Stimulants / Q000378:metabolism*; D015179:Colorectal Neoplasms / Q000209:etiology / Q000235:genetics*; D065637:Cytochrome P-450 CYP2A6; D003577:Cytochrome P-450 Enzyme System / Q000009:adverse effects* / Q000494:pharmacology*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000009:adverse effects* / Q000494:pharmacology*; D010641:Phenotype; D012307:Risk Factors; D013806:Theophylline / Q000652:urine; D014527:Uric Acid / Q000031:analogs & derivatives* / Q000652:urine
chemical_list: D015415:Biomarkers; D000697:Central Nervous System Stimulants; D014527:Uric Acid; D002110:Caffeine; D003577:Cytochrome P-450 Enzyme System; D013806:Theophylline; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C585710:CYP2A6 protein, human; D065637:Cytochrome P-450 CYP2A6; C021183:1,7-dimethylxanthine; C053084:1,7-dimethyluric acid