title: Novel markers of susceptibility to carcinogens in diet: associations with colorectal cancer.
abstract: Red meats cooked at high temperatures generate mutagenic heterocyclic amines, which undergo metabolic activation by hepatic cytochrome P450 1A2 and N-acetyltransferase-2. A primary detoxification pathway involves glutathione S-transferase A1 (GSTA1), which catalyzes the reduction of the carcinogenic N-acetoxy derivative back to the parent amine. Recently, we described a polymorphism in the GSTA1 proximal promoter; the variant (GSTA1*B) allele significantly lowers enzyme expression. In a case-control study, GSTA1*B/*B genotype was associated with an increased risk of colorectal cancer, particularly among consumers of well-done meat. Dietary nitrosamines, which are bioactivated by CYP2A6, represent another potential etiologic factor for colorectal cancer. CYP2A6 converts the caffeine metabolite 1,7-dimethylxanthine (17X) to 1,7-dimethyluric acid (17U); we investigated CYP2A6 activity using the 17U/17X urinary metabolite ratio from case-control subjects who completed a caffeine phenotype assay. The distribution of CYP2A6 activity was significantly different between CRCa cases and controls, with subjects in the medium and high activity groups having an increased risk (P for trend=0.001). GSTA1 genotype and CYP2A6 phenotype should be evaluated as markers of susceptibility to dietary carcinogens in future studies.
authors.affiliation: Division of Molecular Epidemiology, National Center for Toxicological Research, Food and Drug Administration, Jefferson, AR 72079, USA.
authors.forename: Carol
authors.initials: C
authors.lastname: Sweeney
authors.forename: Brian F
authors.initials: BF
authors.lastname: Coles
authors.forename: Susan
authors.initials: S
authors.lastname: Nowell
authors.forename: Nicholas P
authors.initials: NP
authors.lastname: Lang
authors.forename: Fred F
authors.initials: FF
authors.lastname: Kadlubar
mesh_terms: D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics; D001426:Bacterial Proteins; D015415:Biomarkers; D002110:Caffeine; D002273:Carcinogens / Q000633:toxicity*; D002352:Carrier Proteins / Q000235:genetics; D016022:Case-Control Studies; D015179:Colorectal Neoplasms / Q000139:chemically induced* / Q000453:epidemiology*; D065637:Cytochrome P-450 CYP2A6; D004247:DNA / Q000032:analysis / Q000235:genetics; D004032:Diet / Q000009:adverse effects*; D005838:Genotype; D005982:Glutathione Transferase; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008214:Lymphocytes / Q000737:chemistry; D008460:Meat / Q000009:adverse effects / Q000032:analysis*; D006899:Mixed Function Oxygenases / Q000235:genetics; D009602:Nitrosamines / Q000032:analysis; D010641:Phenotype; D010726:Phosphodiesterase Inhibitors; D011401:Promoter Regions, Genetic / Q000235:genetics; D018570:Risk Assessment
chemical_list: D001426:Bacterial Proteins; D015415:Biomarkers; D002273:Carcinogens; D002352:Carrier Proteins; C105760:GstA protein, bacteria; D047908:Intracellular Signaling Peptides and Proteins; D009602:Nitrosamines; D010726:Phosphodiesterase Inhibitors; D002110:Caffeine; D004247:DNA; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C585710:CYP2A6 protein, human; D065637:Cytochrome P-450 CYP2A6; C484555:GSTA1 protein, human; D005982:Glutathione Transferase