Possible impact of human CYP2E1 polymorphisms on the metabolism of acrylonitrile.
Case reports of human accidental poisonings point to significant individual differences in human acrylonitrile metabolism and toxicity. A cohort of 59 persons with industrial handling of low levels of acrylonitrile has repetitively been studied from 1994 through 1999 as part of a medical surveillance programme. The analyses included adduct determinations of N-terminal N-(cyanoethyl)valine in haemoglobin and genotypings of the following cytochrome P-450 2E1 (CYP2E1) polymorphisms: G-1259C and C-1019T (two subjects heterozygous), A-316G (three subjects heterozygous), T-297A (15 subjects heterozygous), G-35T (eight subjects heterozygous), G4804A (two subjects heterozygous), T7668A (six subjects heterozygous). N-(Cyanoethyl)valine adduct levels were, if any, only slightly influenced by smoking and mainly determined by the external acrylonitrile exposures. The individual means and medians of N-(cyanoethyl)valine levels over the entire observation period were compared with the CYP2E1 variants (Wilcoxon rank sum test). No influences of the investigated CYP2E1 polymorphisms on the N-(cyanoethyl)valine levels appeared at the 5% level. However, there was a trend, at a level of P approximately 0.1, pointing to higher acrylonitrile-specific adduct levels in persons with the A-316G mutation. Higher adduct levels would be compatible with a slower CYP2E1-mediated metabolism of acrylonitrile and with lower extents of toxification to cyanide.
Thier
Ricarda
R
Department Physiology and Pharmacology, University of Queensland, St Lucia, Qld 4072, Australia.
Lewalter
Jürgen
J
Selinski
Silvia
S
Bolt
Hermann M
HM
D000181:Acrylonitrile / Q000378:metabolism* / Q000633:toxicity; D015331:Cohort Studies; D019392:Cytochrome P-450 CYP2E1 / Q000235:genetics* / Q000378:metabolism; D004247:DNA / Q000737:chemistry / Q000302:isolation & purification; D006801:Humans; D016273:Occupational Exposure / Q000009:adverse effects; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic / Q000502:physiology*; D012150:Polymorphism, Restriction Fragment Length; D012907:Smoking; D018709:Statistics, Nonparametric
D004247:DNA; D019392:Cytochrome P-450 CYP2E1; D000181:Acrylonitrile