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Hemoglobin Adducts from Acrylonitrile and Ethylene Oxide in Cigarette Smokers: Effects of Glutathione S-Transferase T1-Null and M1-Null Genotypes

Chemical Industry Institute of Toxicology, Research Triangle Park, North Carolina 27709 [T. R. F., J. P. M.]; National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709 [M. W., C. L. T., D. A. B.]; and Analytical Sciences, Inc., Durham, North Carolina 27713 [R. W. M.]

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%.

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