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

A cohort of 59 persons with industrial handling of low levels of acrylonitr ile is being studied as part of a medical surveillance programme. Previousl y, an extended haemoglobin adduct monitoring (N-(cyanoethyl)valine and N-(h ydroxyethyl)-valine) was performed regarding the glutathione transferases h GSTM1 and hGSTT1 polymorphisms but no influence of hGSTM1 or hGSTT1 polymor phisms on specific adduct levels was found. A compilation of case reports o f human accidental poisonings had pointed to significant individual differe nces in human acrylonitrile metabolism and toxicity. Therefore, a re-evalua tion of the industrial cohort included known polymorphisms of the glutathio ne transferases hGSTM3 and hGSTP1 as well as of the cytochrome P450 CYP2E1. A detailed statistical analysis revealed that exposed carriers of the alle lic variants of hGSTP1, hGSTP1*B/hGSTP1*C, characterized by a single nucleo tide polymorphism at nucleotide 313 which results in a change from Ile to V al at codon 104, had higher levels of the acrylonitrile-specific haemoglobi n adduct N-(cyanoethyl)valine compared to the carriers of the codon 113 all eles hGSTP1*A and hGSTP1*D. The single nucleotide polymorphism at codon 113 of hGSTP1 (hGSTP1*A/hGSTP1*B versus hGSTP1*C/hGSTP1*D) did not show an eff ect, and also no influence was seen on specific haemoglobin adduct levels o f the polymorphisms of hGSTM3 or CYP2E1. The data, therefore, point to a po ssible influence of a human enzyme polymorphism of the GSTP1 gene at codon 104 on the detoxication of acrylonitrile which calls for experimental toxic ological investigation. The study also confirmed the impact of GSTT1 polymo rphism on background N-(hydroxyethyl)-valine adduct levels in haemoglobin w hich are caused by endogenous ethylene oxide. (C) 2001 Elsevier Science B.V . All rights reserved.