Comparison of Polymorphisms in Genes Involved in Polycyclic Aromatic Hydrocarbon Metabolism with Urinary Phenanthrene Metabolite Ratios in Smokers

• Published in: Cancer epidemiology, biomarkers & prevention Vol. 15; no. 10; pp. 1805 - 1811
• Main Authors: Hecht, Stephen S, Carmella, Steven G, Yoder, Andrea, Chen, Menglan, Li, Zhong-ze, Le, Chap, Dayton, Rachel, Jensen, Joni, Hatsukami, Dorothy K
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01-10-2006
• Subjects: Adolescent; Adult; Aged; Analysis of Variance; Aryl Hydrocarbon Hydroxylases - genetics; Biological and medical sciences; Biomarkers, Tumor - genetics; Biomarkers, Tumor - urine; cigarette smokers; Cytochrome P-450 CYP1A1 - genetics; Cytochrome P-450 CYP1B1; Epoxide Hydrolases - genetics; Female; Genotype; Glutathione S-Transferase pi - genetics; Glutathione Transferase - genetics; Humans; Lung Neoplasms - epidemiology; Lung Neoplasms - etiology; Lung Neoplasms - genetics; Lung Neoplasms - metabolism; Male; Medical sciences; Middle Aged; Minnesota; phenanthrene metabolism; Phenanthrenes - urine; polycyclic aromatic hydrocarbons; Polycyclic Aromatic Hydrocarbons - metabolism; Polycyclic Aromatic Hydrocarbons - urine; Polymorphism, Genetic; polymorphisms; Predictive Value of Tests; Risk Factors; Smoking - adverse effects; Smoking - genetics; Smoking - metabolism; Tobacco, tobacco smoking; Toxicology; Tumors; Human; Urine; Phenanthrene; Genetic variability; Metabolite; Tobacco smoking; Genotype; Polycyclic aromatic compound; Metabolism; Carcinogen; Cancerology; Gene; Smoker; Genetics; Ratio; Public health; Comparative study; Polymorphism
• ISSN: 1055-9965; 1538-7755
• DOI: 10.1158/1055-9965.EPI-06-0173

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: CYP1A1Msp I, CYP1A1 I462V, CYP1B1 R48G, CYP1B1 A119S, CYP1B1 L432V, CYP1B1 N453S, EPHX1 Y113H, EPHX1 H139R, GSTP1 I105V, GSTP1 A114V, 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 ≥9.90. We found a significant association between the presence of the CYP1A1 I462V 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 CYP1B1 R48G and CYP1B1 A119S 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
CYP1A1 I462 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. (Cancer Epidemiol Biomarkers
Prev 2006;15(10):1805–11)