title: Comparison of polymorphisms in genes involved in polycyclic aromatic hydrocarbon metabolism with urinary phenanthrene metabolite ratios in smokers.
abstract: The hypothesis that interindividual differences among smokers in the metabolism of polycyclic aromatic hydrocarbons (PAH) are related to lung cancer risk has been extensively investigated in the literature. These studies have compared lung cancer risk in groups of smokers with or without polymorphisms in genes involved in PAH metabolism. We believe that carcinogen metabolite phenotyping, involving the actual measurement of PAH metabolites, would be a better way to investigate differences in lung cancer risk. With this goal in mind, we have developed methods for quantifying phenanthrene metabolites in urine. Phenanthrene is the simplest PAH with a bay region, a feature closely associated with carcinogenicity. The urinary metabolite r-1,t-2,3,c-4-tetrahydroxy-1,2,3,4-tetrahydrophenanthrene (PheT) is a measure of metabolic activation, whereas phenanthrols (HOPhe) are a measure of detoxification. In this study, we quantified urinary PheT/HOPhe ratios in 346 smokers who were also genotyped for 11 polymorphisms in genes involved in PAH metabolism: CYP1A1MspI, CYP1A1I462V, CYP1B1R48G, CYP1B1A119S, CYP1B1L432V, CYP1B1N453S, EPHX1Y113H, EPHX1H139R, GSTP1I105V, GSTP1A114V, and GSTM1 null. The geometric mean molar PheT/3-HOPhe ratio was 4.08 (95% confidence interval, 3.79-4.39). Ten percent of the smokers had PheT/3-HOPhe ratios of > or =9.90. We found a significant association between the presence of the CYP1A1I462V polymorphism and high PheT/3-HOPhe ratios (P = 0.02). This effect was particularly strong in females and in combination with the GSTM1 null polymorphism. In contrast, the CYP1B1R48G and CYP1B1A119S polymorphisms were associated with significantly lower PheT/3-HOPhe ratios, particularly in Blacks. There were no consistent significant effects of any of the other polymorphisms on PheT/3-HOPhe ratios. The highest 10% of PheT/3-HOPhe ratios could not be predicted by the presence of any of the 11 polymorphisms individually or by certain combinations. The effects of the CYP1A1I462 polymorphism observed here, particularly in combination with GSTM1 null, are quite consistent with reports in the literature. However, the results of this study indicate that genotyping is not an effective way to predict PAH metabolism at least as represented by PheT/HOPhe ratios.
authors.affiliation: Transdisciplinary Tabacco Use Research Center and The Cancer Center, University of Minnesota, 420 Delaware Street Southeast, Minneapolis, MN 55455, USA. hecht002@umn.edu
authors.forename: Stephen S
authors.initials: SS
authors.lastname: Hecht
authors.forename: Steven G
authors.initials: SG
authors.lastname: Carmella
authors.forename: Andrea
authors.initials: A
authors.lastname: Yoder
authors.forename: Menglan
authors.initials: M
authors.lastname: Chen
authors.forename: Zhong-ze
authors.initials: ZZ
authors.lastname: Li
authors.forename: Chap
authors.initials: C
authors.lastname: Le
authors.forename: Rachel
authors.initials: R
authors.lastname: Dayton
authors.forename: Joni
authors.initials: J
authors.lastname: Jensen
authors.forename: Dorothy K
authors.initials: DK
authors.lastname: Hatsukami
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000704:Analysis of Variance; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics; D014408:Biomarkers, Tumor / Q000235:genetics / Q000652:urine; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics; D065633:Cytochrome P-450 CYP1B1; D004851:Epoxide Hydrolases / Q000235:genetics; D005260:Female; D005838:Genotype; D051549:Glutathione S-Transferase pi / Q000235:genetics; D005982:Glutathione Transferase / Q000235:genetics; D006801:Humans; D008175:Lung Neoplasms / Q000453:epidemiology / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D008910:Minnesota; D010616:Phenanthrenes / Q000652:urine; D011084:Polycyclic Aromatic Hydrocarbons / Q000378:metabolism* / Q000652:urine; D011110:Polymorphism, Genetic; D011237:Predictive Value of Tests; D012307:Risk Factors; D012907:Smoking / Q000009:adverse effects / Q000235:genetics* / Q000378:metabolism*
chemical_list: D001189:Aryl Hydrocarbon Hydroxylases; D014408:Biomarkers, Tumor; D019363:Cytochrome P-450 CYP1A1; D065633:Cytochrome P-450 CYP1B1; D004851:Epoxide Hydrolases; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase; D010616:Phenanthrenes; D011084:Polycyclic Aromatic Hydrocarbons; C585496:CYP1B1 protein, human; C496556:GSTP1 protein, human