The cytochrome P-450 isoenzyme CYP2E1 in the biological processing of industrial chemicals : consequences for occupational and environmental medicine

Bolt, Hermann M., Roos, Peter H., & Thier, Ricarda (2003) The cytochrome P-450 isoenzyme CYP2E1 in the biological processing of industrial chemicals : consequences for occupational and environmental medicine. International Archives of Occupational and Environmental Health, 76(3), pp. 174-185.

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Abstract

The importance of the isoform CYP2E1 of the human cytochrome P-450 superfamily of enzymes for occupational and environmental medicine is derived from its unique substrate spectrum that includes a number of highly important high-production chemicals, such as aliphatic and aromatic hydrocarbons, solvents and industrial monomers (i.a. alkanes, alkenes, aromatic and halogenated hydrocarbons). Many polymorphic genes, such as CYP2E1, show considerable differences in allelic distribution between different human populations. The polymorphic nature of the human CYP2E1 gene is significant for inter-individual differences in toxicity of its substrates. Since the substrate spectrum of CYP2E1 includes many compounds of basic relevance to industrial toxicology, a rationale for metabolic interactions of different CYP2E1 substrates is provided. In-depth research into the inter-individual phenotypic differences of human CYP2E1 enzyme activities was enabled by the recognition that the 6-hydroxylation of the drug chlorzoxazone is mediated by CYP2E1. Studies on CYP2E1 phenotyping have pointed to inter-individual variations in enzyme activities. There are consistent ethnic differences in CYP2E1 enzyme expression, mostly demonstrated between European and Japanese populations, which point to a major impact of genetic factors. The most frequently studied genetic polymorphisms are the restriction fragment length polymorphisms PstI/RsaI (mutant allele: CYP2E15B) located in the 5′-flanking region of the gene, as well as the DraI polymorphism (mutant allele: CYP2E16) located in intron 6. These polymorphisms are partly related, as they form the common allele designated CYP2E15A. Striking inter-ethnic differences between Europeans and Asians appear with respect to the frequencies of the CYP2E15A allele (only approximately 5% of Europeans are heterozygous, but 37% of Asians are, whilst 6% of Asians are homozygous). Available studies indicate a wide variation in human CYP2E1 expression, which are very likely based on complex gene-environment interactions. Major inter-ethnic differences are apparent on the genotyping and the phenotyping levels. Selected cases are presented where inter-ethnic variations of CYP2E1 may provide likely explanations for unexplained findings concerning industrial chemicals that are CYP2E1 substrates. Possible consequences of differential inter-individual and inter-ethnic susceptibilities are related to individual expressions of clinical symptoms of chemical toxicity, to results of biological monitoring of exposed workers, and to the interpretation of results of epidemiological or molecular-epidemiological studies.

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ID Code: 77441
Item Type: Journal Article
Refereed: Yes
Additional URLs:
Keywords: Acrylamide, Acrylonitrile, CYP2E1, Cytochrome P-450, Industrial chemicals, Inter-ethnic variability, Inter-individual variability, n-Hexane, 1, 3-butadiene, 1, 3 butadiene, acetaldehyde, acetone, acetylsalicylic acid, alcohol, aliphatic hydrocarbon, alkane derivative, alkene derivative, aniline, aromatic hydrocarbon, caffeine, chlorzoxazone, clomethiazole, cytochrome P450 2E1, dapsone, disulfiram, enflurane, fatty acid, glycerol, halogenated hydrocarbon, hexane, paracetamol, pyrazole, solvent, styrene, trichloroethylene, unindexed drug, vinyl chloride, acute toxicity, allele, Asian, biological monitoring, chemical industry, DNA flanking region, drug hydroxylation, environmental parameters, enzyme activity, enzyme inhibition, epidemiological data, ethnic difference, Europe, gene frequency, gene mutation, genetic polymorphism, genetic variability, genotype, heredity, human, intron, Japan, nonhuman, occupational exposure, occupational hazard, occupational medicine, phenotype, population, protein expression, review, toxicity, worker, Alleles, Animals, Butadienes, Continental Population Groups, Cytochrome P-450 CYP2E1, Environmental Pollutants, Enzyme Activation, Hexanes, Humans, Organic Chemicals, Poisoning, Polymorphism, Genetic, Polymorphism, Restriction Fragment Length, Variation (Genetics)
DOI: 10.1007/s00420-002-0407-4
ISSN: 0340-0131
Divisions: Current > Schools > School of Clinical Sciences
Current > QUT Faculties and Divisions > Faculty of Health
Copyright Owner: Copyright 2003 Springer-Verlag
Deposited On: 21 Oct 2014 03:01
Last Modified: 22 Oct 2014 00:51

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