title: Genetic polymorphisms and benzene metabolism in humans exposed to a wide range of air concentrations.
abstract: Using generalized linear models with natural-spline smoothing functions, we detected effects of specific xenobiotic metabolizing genes and gene-environment interactions on levels of benzene metabolites in 250 benzene-exposed and 136 control workers in Tianjin, China (for all individuals, the median exposure was 0.512 p.p.m. and the 10th and 90th percentiles were 0.002 and 6.40 p.p.m., respectively). We investigated five urinary metabolites (E,E-muconic acid, S-phenylmercapturic acid, phenol, catechol, and hydroquinone) and nine polymorphisms in seven genes coding for key enzymes in benzene metabolism in humans {cytochrome P450 2E1 [CYP2E1, rs2031920], NAD(P)H: quinone oxidoreductase [NQO1, rs1800566 and rs4986998], microsomal epoxide hydrolase [EPHX1, rs1051740 and rs2234922], glutathione-S-transferases [GSTT1, GSTM1 and GSTP1(rs947894)] and myeloperoxidase [MPO, rs2333227]}. After adjusting for covariates, including sex, age, and smoking status, NQO1*2 (rs1800566) affected all five metabolites, CYP2E1 (rs2031920) affected most metabolites but not catechol, EPHX1 (rs1051740 or rs2234922) affected catechol and S-phenylmercapturic acid, and GSTT1 and GSTM1 affected S-phenylmercapturic acid. Significant interactions were also detected between benzene exposure and all four genes and between smoking status and NQO1*2 and EPHX1 (rs1051740). No significant effects were detected for GSTP1 or MPO. Results generally support prior associations between benzene hematotoxicity and specific gene mutations, confirm earlier evidence that GSTT1 affects production of S-phenylmercapturic acid, and provide additional evidence that genetic polymorphisms in NQO1*2, CYP2E1, and EPHX1 (rs1051740 or rs2234922) affect metabolism of benzene in the human liver.
authors: School of Public Health, University of North Carolina, Chapel Hill, NC 27599, USA.
authors: Sungkyoon
authors: S
authors: Kim
authors: Qing
authors: Q
authors: Lan
authors: Suramya
authors: S
authors: Waidyanatha
authors: Stephen
authors: S
authors: Chanock
authors: Brent A
authors: BA
authors: Johnson
authors: Roel
authors: R
authors: Vermeulen
authors: Martyn T
authors: MT
authors: Smith
authors: Luoping
authors: L
authors: Zhang
authors: Guilan
authors: G
authors: Li
authors: Min
authors: M
authors: Shen
authors: Songnian
authors: S
authors: Yin
authors: Nathaniel
authors: N
authors: Rothman
authors: Stephen M
authors: SM
authors: Rappaport
mesh_terms: D000293:Adolescent; D000328:Adult; D000388:Air; D001554:Benzene / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism*; D001555:Benzene Derivatives / Q000652:urine; D003710:Demography; D004781:Environmental Exposure; D005260:Female; D006801:Humans; D008297:Male; D008954:Models, Biological; D011110:Polymorphism, Genetic
chemical_list: D001555:Benzene Derivatives; D001554:Benzene