Benzene Uptake and Glutathione S-transferase T1 Status as Determinants of S-Phenylmercapturic Acid in Cigarette Smokers in the Multiethnic Cohort

Abstract

Research from the Multiethnic Cohort (MEC) demonstrated that, for the same quantity of cigarette smoking, African Americans and Native Hawaiians have a higher lung cancer risk than Whites, while Latinos and Japanese Americans are less susceptible. We collected urine samples from 2,239 cigarette smokers from five different ethnic groups in the MEC and analyzed each sample for S-phenylmercapturic acid (SPMA), a specific biomarker of benzene uptake. African Americans had significantly higher (geometric mean [SE] 3.69 [0.2], p<0.005) SPMA/ml urine than Whites (2.67 [0.13]) while Japanese Americans had significantly lower levels than Whites (1.65 [0.07], p<0.005). SPMA levels in Native Hawaiians and Latinos were not significantly different from those of Whites. We also conducted a genome-wide association study in search of genetic risk factors related to benzene exposure. The glutathione S-transferase T1 (GSTT1) deletion explained between 14.2–31.6% (p = 5.4x10-157) and the GSTM1 deletion explained between 0.2%-2.4% of the variance (p = 1.1x10-9) of SPMA levels in these populations. Ethnic differences in levels of SPMA remained strong even after controlling for the effects of these two deletions. These results demonstrate the powerful effect of GSTT1 status on SPMA levels in urine and show that uptake of benzene in African American, White, and Japanese American cigarette smokers is consistent with their lung cancer risk in the MEC. While benzene is not generally considered a cause of lung cancer, its metabolite SPMA could be a biomarker for other volatile lung carcinogens in cigarette smoke.

2-Phenethyl Isothiocyanate, Glutathione S-transferase M1 and T1 Polymorphisms, and Detoxification of Volatile Organic Carcinogens and Toxicants in Tobacco Smoke

“…We and others have previously shown that GSTT1 null status has a strong effect on levels of SPMA (26, 27), and that was also observed in this study, where levels of SPMA were significantly lower in GSTT1 null individuals than in non-nulls (Table 3). The 95.4% increase in SPMA in these individuals may be due to PEITC effects on GSTP1 , which is a good catalyst of SPMA formation from benzene oxide (28).…”

“…The analyses for the mercapturic acids were carried out essentially as described previously (21, 22). The limits of quantitation were 0.15 pmol/ml for SPMA, 20 pmol/ml for HPMA, and 12 pmol/ml for HMPMA.…”

Genetic Determinants of 1,3-Butadiene Metabolism and Detoxification in Three Populations of Smokers with Different Risks of Lung Cancer

“…These results correlate with the high lung cancer risk of African Americans and low lung cancer risk of Japanese Americans as compared to Whites, suggesting that BD could play a role in the differences in lung cancer etiology seen between these groups (3). Interestingly, a similar trend was recently reported for mercapturic acids derived from acrolein, crotonaldehyde, and benzene (51,61). Furthermore, levels of the mercapturic acid formed from benzene were strongly influenced by GSTT1 deletion, highlighting the important role of this GST gene in the detoxification of structurally distinct carcinogens (61).…”

“…Interestingly, a similar trend was recently reported for mercapturic acids derived from acrolein, crotonaldehyde, and benzene (51,61). Furthermore, levels of the mercapturic acid formed from benzene were strongly influenced by GSTT1 deletion, highlighting the important role of this GST gene in the detoxification of structurally distinct carcinogens (61). …”

Tobacco, e-cigarettes, and child health

“…This is a situation where biomarkers studies might provide insight into the tobacco smoke chemicals that are contributing to the adverse birth outcomes. For example, GSTT1 null genotype influences the levels of urinary benzene and 1,3-butadiene metabolites in smokers [22,23]. CYP1A1 and GSTT1 variants affect metabolite levels of a model polycyclic aromatic hydrocarbon, phenanthrene [24,25].…”