Benzene oxide is a substrate for glutathione S-transferases

Zarth, Adam T.; Murphy, Sharon E.; Hecht, Stephen S.

doi:10.1016/j.cbi.2015.11.005

Cited by 17 publications

(17 citation statements)

References 40 publications

(36 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…While this effect of genotype has been noted before, our study is the largest and most definitive [ 31 – 40 ]. The stronger effect of GSTT1 than GSTM1 deletion observed here is consistent with our metabolic studies which demonstrate that GSTT1 is a better catalyst of benzene oxide conjugation than GSTM1 [ 54 ]. The size of our study allowed us to analyze ethnic differences in SPMA levels correcting for each genotype.…”

Section: Discussionsupporting

confidence: 92%

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

et al. 2016

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionsupporting

confidence: 92%

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

et al. 2016

Self Cite

View full text Add to dashboard Cite

show abstract

“…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). GSTP1 is also an excellent catalyst of acrolein and crotonaldehyde conjugation with glutathione (29) and induction of this enzyme may contribute to the effects of PEITC on the urinary levels of HPMA and HMPMA.…”

Section: Discussionmentioning

confidence: 99%

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

Yuan

Murphy

Stepanov

et al. 2016

Cancer Prevention Research

Self Cite

View full text Add to dashboard Cite

Cigarette smoke contains relatively large quantities of volatile organic toxicants or carcinogens such as benzene, acrolein and crotonaldehyde. Among their detoxification products are mercapturic acids formed from glutathione conjugation, catalyzed in part by glutathione S-transferases (GST). A randomized phase 2 clinical trial with a crossover design was conducted to evaluate the effect of 2-phenethyl isothiocyanate (PEITC), a natural product formed from gluconasturtiin in certain cruciferous vegetables, on the detoxification of benzene, acrolein, and crotonaldehyde in 82 cigarette smokers. Urinary mercapturic acids of benzene, acrolein and crotonaldehyde at baseline and during treatment were quantified. Overall, oral PEITC supplementation increased the mercapturic acid formed from benzene by 24.6% (P=0.002) and acrolein by 15.1% (P=0.005), but had no effect on crotonaldehyde. A remarkably stronger effect was observed among subjects with the null genotype of both GSTM1 and GSTT1: in these individuals PEITC increased the detoxification metabolite of benzene by 95.4% (P<0.001), of acrolein by 32.7% (P=0.034), and of crotonaldehyde by 29.8% (P=0.006). In contrast, PEITC had no effect on these mercapturic acids in smokers possessing both genes. PEITC had no effect on the urinary oxidative stress biomarker 8-iso-prostaglandin F2α or the inflammation biomarker prostaglandin E2 metabolite. This trial demonstrates an important role of PEITC in detoxification of environmental carcinogens and toxicants which also occur in cigarette smoke. The selective effect of PEITC on detoxification in subjects lacking both GSTM1 and GSTT1 genes supports the epidemiological findings of stronger protection by dietary isothiocyanates against the development of lung cancer in such individuals.

show abstract

“…Pooled HLC (1 mg) was added to a reaction containing 100 mM potassium phosphate (pH = 7.4) and 250 μ M EXE or 335 μ M 17 β -DHE in a total volume of 1 ml. The reaction mixture was preincubated at 37°C for 3 minutes prior to the addition of 50 µ l of 100 mM GSH (final GSH concentration = 5 mM) ( Lash et al, 1999 ; Zarth et al, 2015 ; Shi et al, 2016 ). After 2 hours at 37°C, the reaction was stopped with an equal reaction volume of ice-cold acetonitrile and centrifuged at 16,100 g for 10 minutes at 4°C.…”

Section: Methodsmentioning

confidence: 99%

Identification and Quantification of Novel Major Metabolites of the Steroidal Aromatase Inhibitor, Exemestane

et al. 2018

View full text Add to dashboard Cite

Exemestane (EXE) is an aromatase inhibitor used for the prevention and treatment of estrogen receptor-positive breast cancer. Although the known major metabolic pathway for EXE is reduction to form the active 17b-dihydro-EXE (17b-DHE) and subsequent glucuronidation to 17b-hydroxy-EXE-17-O-b-D-glucuronide (17b-DHE-Gluc), previous studies have suggested that other major metabolites exist for exemestane. In the present study, a liquid chromatography-mass spectrometry (LC-MS) approach was used to acquire accurate mass data in MS E mode, in which precursor ion and fragment ion data were obtained simultaneously to screen novel phase II EXE metabolites in urine specimens from women taking EXE. Two major metabolites predicted to be cysteine conjugates of EXE and 17b-DHE by elemental composition were identified. The structures of the two metabolites were confirmed to be 6-methylcysteinylandrosta-1,4-diene-3,17-dione (6-EXE-cys) and 6-methylcysteinylandrosta-1,4-diene-17b-hydroxy-3-one (6-17b-DHE-cys) after comparison with their chemically synthesized counterparts. Both underwent biosynthesis in vitro in three stepwise enzymatic reactions, with the first involving glutathione conjugation. The cysteine conjugates of EXE and 17b-DHE were subsequently quantified by liquid chromatography-mass spectrometry in the urine and matched plasma samples of 132 subjects taking EXE. The combined 6-EXE-cys plus 6-17b-DHE-cys made up 77% of total EXE metabolites in urine (vs. 1.7%, 0.14%, and 21% for EXE, 17b-DHE, and 17b-DHE-Gluc, respectively) and 35% in plasma (vs. 17%, 12%, and 36% for EXE, 17b-DHE, and 17b-DHE-Gluc, respectively).

show abstract

Benzene oxide is a substrate for glutathione S-transferases

Cited by 17 publications

References 40 publications

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

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

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

Identification and Quantification of Novel Major Metabolites of the Steroidal Aromatase Inhibitor, Exemestane

Contact Info

Product

Resources

About