Association of genetic polymorphisms in CYP2E1, MPO, NQO1, GSTM1, and GSTT1 genes with benzene poisoning.
Metabolic enzymes involved in benzene activation or detoxification, including NAD(P)H, quinone oxidoreductase 1 (NQO1), cytochrome P450 2E1 (CYP2E1), myeloperoxidase (MPO), glutathione-S-transferase mu-1 (GSTM1), and glutathione-S-transferase theta-1 (GSTT1), were studied for their roles in human susceptibility to benzene poisoning. The potential interactions of these metabolic enzymes with lifestyle factors such as cigarette smoking and alcohol consumption were also explored. We studied 156 benzene-poisoning patients and 152 workers occupationally exposed to benzene in South China. Sequencing, denaturing HPLC, restriction fragment-length polymorphism, and polymerase chain reaction were used to detect polymorphisms on the promoters and complete coding regions of NQO1, CYP2E1, MPO, and the null genotypes of GSTM1 and GSTT1. Seventeen single nucleotide polymorphisms (SNPs) were identified in NQO1, CYP2E1, and MPO genes, including 6 novel SNPs in CYP2E1 and MPO. Of the subjects who smoked and drank alcohol, an 8.15-fold [95% confidence interval (CI), 1.43-46.50] and a 21.50-fold (95% CI, 2.79-165.79) increased risk of benzene poisoning, respectively, were observed among the subjects with two copies of NQO1 with a C-to-T substitution in cDNA at nucleotide 609 (c.609 C>T variation; i.e., NQO1 c.609 T/T) compared to those with the heterozygous or wild (NQO1 c.609 C/T and c.609 C/C) genotypes. Our data also indicated that individuals with CYP2E1 c.-1293 C/C and c.-1293 G/C, and NQO1 c.609 T/T, and GSTT1 null genotypes tended to be more susceptible to benzene toxicity. Our results suggest that the combined effect of polymorphisms in NQO1, CYP2E1, and GSTT1 genes and lifestyle factors might contribute to benzene poisoning.
Wan
Junxiang
J
Department of Occupational and Environmental Health, School of Public Health, Fudan University, Shanghai, China.
Shi
Jinxiu
J
Hui
Lijian
L
Wu
Dan
D
Jin
Xipeng
X
Zhao
Naiqing
N
Huang
Wei
W
Xia
Zhaolin
Z
Hu
Gengxi
G
D001554:Benzene / Q000378:metabolism* / Q000506:poisoning*; D002851:Chromatography, High Pressure Liquid; D019392:Cytochrome P-450 CYP2E1 / Q000096:biosynthesis / Q000235:genetics* / Q000494:pharmacology; D017931:DNA Primers; D020022:Genetic Predisposition to Disease; D005838:Genotype; D005982:Glutathione Transferase / Q000096:biosynthesis / Q000235:genetics* / Q000494:pharmacology; D006801:Humans; D008019:Life Style; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000096:biosynthesis / Q000235:genetics* / Q000494:pharmacology; D016273:Occupational Exposure; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D012150:Polymorphism, Restriction Fragment Length
D001554:Benzene; D019392:Cytochrome P-450 CYP2E1; D017931:DNA Primers; D005982:Glutathione Transferase; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human; C413545:glutathione S-transferase T1