Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
Influence of polymorphisms of the human glutathione transferases and cytochrome P450 2E1 enzyme on the metabolism and toxicity of ethylene oxide and acrylonitrile
Introduction
Acrylonitrile is an important high-volume chemical in the industrial production of polymers. Besides being debated as a carcinogen [1], its acute toxicity is very high, life-threatening and even fatal intoxications are documented in the literature [2], [3]. A recent compilation of industrial intoxication cases [4] suggested significant interspecies differences in metabolism and toxicity of acrylonitrile between humans and experimental animals, and intraspecies differences between human individuals.
Whereas it is well established that the predominantly relevant cytochrome P450 isozyme in the oxidative pathway of acrylonitrile is CYP2E1 [5], [6], [7], little is known about the relevant isoenzymes of glutathione transferase in the alternative glutathione-dependent pathway. Because polymorphisms of hGSTT1 and hGSTM1 had no apparent influence on the levels of the haemoglobin adduct N-(cyanoethyl)valine in industrial acrylonitrile exposed workers, it has been concluded that hGSTT1 and hGSTM1 were not likely to be involved [8].
As clinical observations in cases of accidental industrial intoxications clearly indicate the likelihood of significant human individual differences in acrylonitrile metabolism and toxicity [4], we further investigated the cohort of workers having industrial contact with acrylonitrile, in which we had previously reported on haemoglobin adduct levels and lacking effects of hGSTT1 and hGSTM1 polymorphisms [8]. With the detection of further human polymorphisms in glutathione transferases, namely of hGSTM3 and hGSTP1 [10], and of novel polymorphisms in the CYP2E1 gene [11], it was possible to include new genomic variants in the study of biomarkers, in search of factors of individual susceptibility towards the deleterious effects of acrylonitrile on human health.
Section snippets
Subjects and study of biomarkers
The present study is a continuation of the study previously reported by Thier et al. [8]. In all, 59 persons with industrial handling of acrylonitrile, at different workplaces and to different extents, were studied in 1994 and 1995. As part of a medical surveillance programme, on different occasions whole blood was collected from each person by venipuncture using EDTA containing syringes (Sarstedt, Germany) and stored at −80°C. The state of smoker or non-smoker was recorded. The actual
Results
Results of haemoglobin adduct monitoring in the 59 subjects with industrial acrylonitrile contact have previously been compiled [8]. The Wilcoxon test was first applied to test for effects of genetic traits on N-(cyanoethyl)valine and N-(hydroxyethyl)-valine adduct levels, the adducts of (exogenous) acrylonitrile and (endogenous) ethylene oxide, respectively, within this cohort. Upon application of this statistical test and of the Kruskal–Wallis test in case of GSTM3, no differences were
Discussion
Acrylonitrile is metabolized via two different pathways [17], [18], [19]; the reductive glutathione-dependent pathway, via Michael addition of glutathione to acrylonitrile, leads to S-(cyanoethyl)glutathione and finally to the respective mercapturic acid which is excreted in the urine. This pathway is considered the relevant route of detoxication [20]. The alternative oxidative pathway leads first to the reactive intermediary epoxide glycidonitrile, most probably the relevant genotoxic
Acknowledgements
The authors thank the Deutsche Forschungs-gemeinschaft (SFB 475) for financial support.
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Present address: Department of Physiology and Pharmacology University of Queensland St Lucia, Queensland, Australia, 4072.