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

Thier, Ricarda, Balkenhol, Heiko, Lewalter, Jürgen, Selinski, Silvia, Dommermuth, Anja, & Bolt, Hermann M. (2001) Influence of polymorphisms of the human glutathione transferases and cytochrome P450 2E1 enzyme on the metabolism and toxicity of ethylene oxide and acrylonitrile. Mutation Research - Fundamental and Molecular Mechanisms of Mutagenesis, 482(1-2), pp. 41-46.

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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.

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ID Code: 77476
Item Type: Journal Article
Refereed: Yes
Keywords: Acrylonitrile, GST polymorphisms, Haemoglobin adducts, cytochrome P450 2E1, ethylene oxide, glutathione transferase, glutathione transferase M1, glutathione transferase m3, glutathione transferase P1, glutathione transferase T1, hemoglobin, isoenzyme, isoleucine, n (cyanoethyl)valine, n (hydroxyethyl)valine, nucleotide, unclassified drug, valine, allele, article, codon, cohort analysis, controlled study, detoxification, DNA polymorphism, enzyme polymorphism, evaluation, genetic variability, human, industrial worker, intoxication, major clinical study, metabolism, monitoring, periodic medical examination, priority journal, statistical analysis, toxicity, Carcinogens, Cytochrome P-450 CYP2E1, DNA Adducts, Glutathione S-Transferase pi, Hemoglobins, Humans, Isoenzymes, Occupational Exposure, Polymorphism, Genetic
DOI: 10.1016/S0027-5107(01)00208-1
ISSN: 0027-5107
Divisions: Current > Schools > School of Clinical Sciences
Current > QUT Faculties and Divisions > Faculty of Health
Copyright Owner: Copyright 2001 Elsevier Science B.V.
Deposited On: 15 Oct 2014 23:27
Last Modified: 15 Oct 2014 23:27

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