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 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, hGSTP1*B/hGSTP1*C, 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 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 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.
Thier
R
R
Institut für Arbeitsphysiologie an der Universität Dortmund, Ardeystr. 67, D-44139 Dortmund, Germany. thier@mailbox.uq.edu.au
Balkenhol
H
H
Lewalter
J
J
Selinski
S
S
Dommermuth
A
A
Bolt
H M
HM
D000181:Acrylonitrile / Q000378:metabolism* / Q000633:toxicity; D002273:Carcinogens / Q000378:metabolism / Q000633:toxicity; D019392:Cytochrome P-450 CYP2E1 / Q000235:genetics*; D018736:DNA Adducts / Q000032:analysis / Q000737:chemistry; D005027:Ethylene Oxide / Q000378:metabolism* / Q000633:toxicity; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase / Q000235:genetics*; D006454:Hemoglobins / Q000737:chemistry; D006801:Humans; D007527:Isoenzymes / Q000235:genetics; D016273:Occupational Exposure; D011110:Polymorphism, Genetic; D014633:Valine / Q000031:analogs & derivatives / Q000097:blood
D000181:Acrylonitrile; D002273:Carcinogens; D019392:Cytochrome P-450 CYP2E1; D018736:DNA Adducts; D005027:Ethylene Oxide; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase; D006454:Hemoglobins; D007527:Isoenzymes; D014633:Valine; C091192:N-(2-cyanoethyl)valine; C057442:2-hydroxyethylvaline; C413545:glutathione S-transferase T1; C496556:GSTP1 protein, human