Influence of polymorphisms of the human glutathione transferases and cytochrome P450 2E1 enzyme on the metabolism and toxicity of ethylene oxide and acrylonitrile

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Abstract

A cohort of 59 persons with industrial handling of low levels of acrylonitrile is being studied as part of a medical surveillance programme. Previously, an extended haemoglobin adduct monitoring (N-(cyanoethyl)valine and N-(hydroxyethyl)-valine) was performed regarding the glutathione transferases hGSTM1 and hGSTT1 polymorphisms but no influence of hGSTM1 or hGSTT1 polymorphisms on specific adduct levels was found. A compilation of case reports of human accidental poisonings had pointed to significant individual differences in human acrylonitrile metabolism and toxicity. Therefore, a re-evaluation of the industrial cohort included known polymorphisms of the glutathione transferases hGSTM3 and hGSTP1 as well as of the cytochrome P450 CYP2E1. A detailed statistical analysis revealed that exposed carriers of the allelic variants of hGSTP1, hGSTP1B/hGSTP1C, characterized by a single nucleotide polymorphism at nucleotide 313 which results in a change from Ile to Val at codon 104, had higher levels of the acrylonitrile-specific haemoglobin adduct N-(cyanoethyl)valine compared to the carriers of the codon 113 alleles hGSTP1A and hGSTP1D. The single nucleotide polymorphism at codon 113 of hGSTP1 (hGSTP1A/hGSTP1B versus hGSTP1C/hGSTP1D) did not show an effect, and also no influence was seen on specific haemoglobin adduct levels of the polymorphisms of hGSTM3 or CYP2E1. The data, therefore, point to a possible influence of a human enzyme polymorphism of the GSTP1 gene at codon 104 on the detoxication of acrylonitrile which calls for experimental toxicological investigation. The study also confirmed the impact of GSTT1 polymorphism on background N-(hydroxyethyl)-valine adduct levels in haemoglobin which are caused by endogenous ethylene oxide.

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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    1

    Present address: Department of Physiology and Pharmacology University of Queensland St Lucia, Queensland, Australia, 4072.

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