Fennell, T. R. et al. Hemoglobin adducts from acrylonitrile and ethylene oxide in cigarette smokers: effects of glutathione-S-transferase T1-null and M1-null genotypes. Cancer Epidemiol. Biomarkers Prev. 9, 705-712
ABSTRACT Acrylonitrile (ACN) is used to manufacture plastics and fibers. It is carcinogenic in rats and is found in cigarette smoke. Ethylene oxide (EO) is a metabolite of ethylene, also found in cigarette smoke, and is carcinogenic in rodents. Both ACN and EO undergo conjugation with glutathione. The objectives of this study were to examine the relationship between cigarette smoking and hemoglobin adducts derived from ACN and EO and to investigate whether null genotypes for glutathione transferase (GSTM1 and GSTT1) alter the internal dose of these agents. The hemoglobin adducts N-(2-cyanoethyl)valine (CEVal), which is formed from ACN, and N-(2-hydroxyethyl)valine (HEVal), which is formed from EO, and GST genotypes were determined in blood samples obtained from 16 nonsmokers and 32 smokers (one to two packs/day). Smoking information was obtained by questionnaire, and plasma cotinine levels were determined by immunoassay. Glutathione transferase null genotypes (GSTM1 and GSTT1) were determined by PCR. Both CEVal and HEVal levels increased with increased cigarette smoking dose (both self-reported and cotinine-based). CEVal and HEVal levels were also correlated. GSTM1 and GSTT1 genotypes had little effect on CEVal concentrations. GSTM1 null genotypes had no significant impact on HEVal. However, HEVal levels were significantly elevated in GSTT1-null individuals when normalized to smoking status or cotinine levels. The ratio of HEVal:CEVal was also elevated in GSTT1-null smokers (1.50 +/- 0.57 versus 0.88 +/- 0.24; P = 0.0002). The lack of a functional GSTT1 is estimated to increase the internal dose of EO derived from cigarette smoke by 50-70%.
- SourceAvailable from: Christian Pütz
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- "The latter enzyme exhibits polymorphism. Fennell et al. (2000) showed in a study on 32 cigarette smokers that HEV levels resulting from ET and/or EO in the smoke were on average 1.61 times higher in glutathione-S-transferase T1 noncarriers (GSTT1*0) than in those individuals carrying the fully active enzyme. In other words, the statistically significant difference in the slopes between volunteers A and C and volunteers B and D may result from the polymorphism of the glutathione-S-transferase T1. "
ABSTRACT: The gaseous olefin ethylene (ET) is metabolized in mammals to the carcinogenic epoxide ethylene oxide (EO). Although ET is the largest volume organic chemical worldwide, the EO burden in ET-exposed humans is still uncertain and only limited data is available on the EO burden in ET-exposed rodents. Therefore, EO was quantified in blood of mice, rats, or four volunteers that were single exposed for 6 h to constant atmospheric ET concentrations of between 1 and 10000 ppm (rodents) or 5 and 50 ppm (humans). Both compounds were determined by gas chromatography. At ET concentrations between 1 and 10000 ppm, areas under the concentration-time curves of EO in blood (Nmol x h/l) ranged from 0.039 to 3.62 in mice and from 0.086 to 11.6 in rats. At ET concentrations ≤30 ppm, EO concentrations in blood were 8.7-fold higher in rats and 3.9-fold higher in mice than in the volunteer with the highest EO burdens. Based on measured EO concentrations, levels of EO adducts to hemoglobin and lymphocyte DNA were calculated for diverse ET concentrations and compared with published adduct levels. For given ET exposure concentrations, there were good agreements between calculated and measured levels of adducts to hemoglobin in rats and humans and to DNA in rats and mice. Reported hemoglobin adduct levels in mice were higher than calculated ones. Furthermore, information is given on species-specific background adduct levels. In summary, the study provides most relevant data for an improved assessment of the human health risk from exposure to ET.Toxicological Sciences 09/2013; 136(2). DOI:10.1093/toxsci/kft218 · 4.48 Impact Factor
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- "This conclusion of a quantitatively relevant role of EH on the elimination of EO in humans is supported by the results of a thoroughly conducted study on smokers. Hydroxyethyl adduct levels to the N-terminal valine of hemoglobin were on average 1.61 times higher in GSTT1- null individuals than in GSTT1 carriers (Fennell et al., 2000). "
ABSTRACT: Ethylene (ET) is metabolized in mammals to the carcinogenic ethylene oxide (EO). Although both gases are of high industrial relevance, only limited data exist on the toxicokinetics of ET in mice and of EO in humans. Metabolism of ET is related to cytochrome P450-dependent mono-oxygenase (CYP) and of EO to epoxide hydrolase (EH) and glutathione S-transferase (GST). Kinetics of ET metabolism to EO and of elimination of EO were investigated in headspace vessels containing incubations of subcellular fractions of mouse, rat, or human liver or of mouse or rat lung. CYP-associated metabolism of ET and GST-related metabolism of EO were found in microsomes and cytosol, respectively, of each species. EH-related metabolism of EO was not detectable in hepatic microsomes of rats and mice but obeyed saturation kinetics in hepatic microsomes of humans. In ET-exposed liver microsomes, metabolism of ET to EO followed Michaelis-Menten-like kinetics. Mean values of V(max) [nmol/(min·mg protein)] and of the apparent Michaelis constant (K(m) [mmol/l ET in microsomal suspension]) were 0.567 and 0.0093 (mouse), 0.401 and 0.031 (rat), and 0.219 and 0.013 (human). In lung microsomes, V(max) values were 0.073 (mouse) and 0.055 (rat). During ET exposure, the rate of EO production decreased rapidly. By modeling a suicide inhibition mechanism, rate constants for CYP-mediated catalysis and CYP inactivation were estimated. In liver cytosol, mean GST activities to EO expressed as V(max)/K(m) [μl/(min·mg protein)] were 27.90 (mouse), 5.30 (rat), and 1.14 (human). The parameters are most relevant for reducing uncertainties in the risk assessment of ET and EO.Toxicological Sciences 07/2011; 123(2):384-98. DOI:10.1093/toxsci/kfr194 · 4.48 Impact Factor
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- "S-Phenylmercapturic acid (S-PMA) is another biomarker of benzene exposure, which is elevated in smokers and appears to have higher specificity than trans, trans-muconic acid (Hecht, 2002; Lin, Tyan, Shih, Chang, & Liao, 2004; Maestri, Negri, Ferrari, Ghittori, & Imbriani, 2005; Melikian et al., 2002; Tharnpoophasiam, Kongtip, Wongwit, Fungladda, & Kitayaporn, 2004). Hb adducts of the carcinogens ethylene oxide, acrylamide, acrylonitrile, and of an unknown ethylating agent are higher in smokers than in nonsmokers but are not specific to tobacco use (Bergmark, 1997; Carmella et al., 2002; Fennell et al., 2000). Effects of smoking cessation have not been "
ABSTRACT: To date, we have no valid biomarkers that serve as proxies for tobacco-related disease to test potential reduced exposure products. This paper represents the deliberations of four workgroups that focused on four tobacco-related heath outcomes: Cancer, nonmalignant pulmonary disease, cardiovascular disease, and fetal toxicity. The goal of these workgroups was to identify biomarkers that offer some promise as measures of exposure or toxicity and ultimately may serve as indicators for future disease risk. Recommendations were based on the relationship of the biomarker to what is known about mechanisms of tobacco-related pathogenesis, the extent to which the biomarker differs among smokers and nonsmokers, and the sensitivity of the biomarker to changes in smoking status. Other promising biomarkers were discussed. No existing biomarkers have been demonstrated to be predictive of tobacco-related disease, which highlights the importance and urgency of conducting research in this area.Nicotine & Tobacco Research 09/2006; 8(4):600-22. DOI:10.1080/14622200600858166 · 2.81 Impact Factor