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 z9.90. 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.

Dose-Response Modeling of Occupational Exposure to Polycyclic Aromatic Hydrocarbons with Biomarkers of Exposure and Effect

“…Other potential confounders, such as age and Caucasian ethnicity, had no relevant effect on hydroxyphenanthrenes in this study (13). In addition, genetic polymorphisms may modulate the individual levels of PAH metabolites (46)(47)(48)(49)(50)(51)(52). We found no clear effect of various sequence variations on the metabolite levels in our study as published elsewhere (13).…”

Susceptibility of Lung Cancer with Polymorphisms of CYP1A1, GSTM1, GSTM3, GSTT1 and GSTP1 Genotypes in the Population of Inner Mongolia Region

“…The second polymorphism is a T"C transition in the 3' non-coding region (Msp1 polymorphism). This polymorphism has been shown to correlate with inducible aryl hydrocarbon hydrolase activity (Hecht et al, 2006). CYP1A1 Msp1 and exon7 polymorphisms are associated with the smoking related lung cancer risk in Kashmiri population (Sheikh et al, 2009).…”

Phenanthrene Metabolism in Smokers: Use of a Two-Step Diagnostic Plot Approach to Identify Subjects with Extensive Metabolic Activation

“…Genotyping was performed by using the iPLEX Gold method (Sequenom, San Diego, CA). Similar methods have been reported previously (Hecht et al, 2006). In brief, the method is based on the primer-extension reaction that generates allele-specific products with distinct masses detected by matrixassisted laser desorption/ionization time-of-flight mass spectrometry.…”