title: Interest of genotyping and phenotyping of drug-metabolizing enzymes for the interpretation of biological monitoring of exposure to styrene.
abstract: 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.
authors.affiliation: Industrial Toxicology and Occupational Medicine Unit, Catholic University of Louvain, Brussels, Belgium. haufroid@toxi.ucl.ac.be
authors.forename: Vincent
authors.initials: V
authors.lastname: Haufroid
authors.forename: Marek
authors.initials: M
authors.lastname: Jakubowski
authors.forename: Beata
authors.initials: B
authors.lastname: Janasik
authors.forename: Danuta
authors.initials: D
authors.lastname: Ligocka
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Buchet
authors.forename: Enrico
authors.initials: E
authors.lastname: Bergamaschi
authors.forename: Paola
authors.initials: P
authors.lastname: Manini
authors.forename: Antonio
authors.initials: A
authors.lastname: Mutti
authors.forename: Sergio
authors.initials: S
authors.lastname: Ghittori
authors.forename: Michael
authors.initials: M
authors.lastname: Arand
authors.forename: Nina
authors.initials: N
authors.lastname: Hangen
authors.forename: Franz
authors.initials: F
authors.lastname: Oesch
authors.forename: Ari
authors.initials: A
authors.lastname: Hirvonen
authors.forename: Dominique
authors.initials: D
authors.lastname: Lison
mesh_terms: D000111:Acetylcysteine / Q000652:urine; D000328:Adult; D015415:Biomarkers / Q000032:analysis*; D019392:Cytochrome P-450 CYP2E1 / Q000235:genetics* / Q000378:metabolism; D004781:Environmental Exposure / Q000032:analysis*; D004784:Environmental Monitoring; D004851:Epoxide Hydrolases / Q000235:genetics / Q000378:metabolism; D005838:Genotype; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase / Q000235:genetics* / Q000378:metabolism; D006038:Glyoxylates / Q000652:urine; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D008214:Lymphocytes / Q000187:drug effects*; D008297:Male; D008333:Mandelic Acids / Q000652:urine; D010641:Phenotype; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D012150:Polymorphism, Restriction Fragment Length; D020058:Styrene / Q000009:adverse effects*
chemical_list: D000111:Acetylcysteine; D015415:Biomarkers; D019392:Cytochrome P-450 CYP2E1; D004851:Epoxide Hydrolases; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase; D006038:Glyoxylates; D007527:Isoenzymes; D008333:Mandelic Acids; D020058:Styrene; C012482:phenylglyoxylic acid; C413545:glutathione S-transferase T1; C496556:GSTP1 protein, human; C037938:mandelic acid