Document Detail

Interest of genotyping and phenotyping of drug-metabolizing enzymes for the interpretation of biological monitoring of exposure to styrene.
MedLine Citation:
PMID:  12464798     Owner:  NLM     Status:  MEDLINE    
In the field of occupational and/or environmental toxicology, the measurement of specific metabolites in urine may serve to assess exposure to the parent compounds (biological monitoring of exposure). Styrene is one of the chemicals for which biological monitoring programs have been validated and implemented in environmental and occupational medicine. However, inter-individual differences in the urinary excretion exist both for the main end-products (mandelic acid and phenylglyoxylic acid) and for its specific mercapturic acids (phenylhydroxyethylmercapturic acids, PHEMA). This limits to a certain extent the use of these metabolites for an accurate assessment of styrene exposure. In a group of 26 volunteers selected with relevant genotypes, and exposed to styrene vapours (50 mg/m3, 8 h) in an inhalation chamber, we evaluated whether genotyping or phenotyping relevant drug-metabolizing enzymes (CYP2E1, EPHX1, GSTM1, GSTT1 and GSTP1) may help to explain the observed inter-individual variability in the urinary metabolite excretion. Peripheral blood lymphocytes were used for genotyping and as reporter cells for the phenotyping of CYP2E1 and EPHX1. The GSTM1 genotype was clearly the most significant parameter explaining the variance in urinary PHEMA excretion (6-fold lower in GSTM1 null subjects; P < 0.0001) so that systematic GSTM1 genotyping should be recommended routinely for a correct interpretation of PHEMA urinary levels. Variant alleles CYP2E1*6 (7632T>A) and His113EPHX1 were associated with a significant reduction of, respectively, the expression (P = 0.047) and activity (P = 0.022) of the enzyme in peripheral blood lymphocytes. In combination with GSTM1 genotyping, the phenotyping approach also contributed to improve the interpretation of urinary results, as illustrated by the combined effect of CYP2E1 expression and GSTM1 allelic status that explained 77% of the variance in PHEMA excretion and allows the recommendation of mercapturates as specific and reliable biomarkers of exposure to styrene.
Vincent Haufroid; Marek Jakubowski; Beata Janasik; Danuta Ligocka; Jean-Pierre Buchet; Enrico Bergamaschi; Paola Manini; Antonio Mutti; Sergio Ghittori; Michael Arand; Nina Hangen; Franz Oesch; Ari Hirvonen; Dominique Lison
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Pharmacogenetics     Volume:  12     ISSN:  0960-314X     ISO Abbreviation:  Pharmacogenetics     Publication Date:  2002 Dec 
Date Detail:
Created Date:  2002-12-04     Completed Date:  2003-07-07     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  9211735     Medline TA:  Pharmacogenetics     Country:  England    
Other Details:
Languages:  eng     Pagination:  691-702     Citation Subset:  IM    
Copyright Information:
Copyright 2002 Lippincott Williams & Wilkins
Industrial Toxicology and Occupational Medicine Unit, Catholic University of Louvain, Brussels, Belgium.
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MeSH Terms
Acetylcysteine / urine
Biological Markers / analysis*
Cytochrome P-450 CYP2E1 / genetics*,  metabolism
Environmental Exposure / analysis*
Environmental Monitoring
Epoxide Hydrolases / genetics,  metabolism
Glutathione S-Transferase pi
Glutathione Transferase / genetics*,  metabolism
Glyoxylates / urine
Isoenzymes / genetics,  metabolism
Lymphocytes / drug effects*
Mandelic Acids / urine
Polymerase Chain Reaction
Polymorphism, Genetic
Polymorphism, Restriction Fragment Length
Styrene / adverse effects*
Reg. No./Substance:
0/Biological Markers; 0/Glyoxylates; 0/Isoenzymes; 0/Mandelic Acids; 100-42-5/Styrene; 611-73-4/phenylglyoxylic acid; 616-91-1/Acetylcysteine; 90-64-2/mandelic acid; EC P-450 CYP2E1; EC 2.5.1.-/glutathione S-transferase T1; EC protein, human; EC S-Transferase pi; EC Transferase; EC S-transferase M1; EC 3.3.2.-/Epoxide Hydrolases

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