Genetic polymorphisms involved in toxicant-metabolizing enzymes and the risk of chronic benzene poisoning in Chinese occupationally exposed populations

Abstract

Benzene is a recognized haematotoxin and leukaemogen, but its mechanism of action and the role of genetic susceptibility are still unclear. Cytochrome P450 2E1 (CYP2E1) and myeloperoxidase (MPO) are involved in benzene activation; and NAD (P)H:quinine oxidoreductase 1 (NQO1), glutathione S-transferase theta 1 (GSTT1) and glutathione S-transferase mu 1 (GSTM1) participate in benzene detoxification. The common, well-studied single-nucleotide polymorphisms (SNPs) were analysed in these genes drawn from the toxicant-metabolizing pathways. A total of 100 workers with chronic benzene poisoning (CBP) and 90 controls were enrolled in China. There was a 2.82-fold (95% CI = 1.42-5.58) increased risk of CBP in the subjects with the NQO1 609C > T mutation genotype (T/T) compared with those carrying heterozygous (C/T) and wild-type (C/C). The subjects with the GSTT1 null genotype had a 1.91-fold (95% CI = 1.05-3.45) increased risk of CBP compared with those with GSTT1 non-null genotype. There was no association of CYP2E1 and MPO genotype with CBP. A three genes' interaction showed that there was a 20.41-fold (95% CI = 3.79-111.11) increased risk of CBP in subjects with the NQO1 609C > T T/T genotype and with the GSTT1 null genotype and the GSTM1 null genotype compared with those carrying the NQO1 609C > T C/T and C/C genotype, GSTT1 non-null genotype, and GSTM1 non-null genotype. The study provides evidence of an association of a gene-gene interaction with the risk of CBP.

Evaluation of urinary biomarkers of exposure to benzene: correlation with blood benzene and influence of confounding factors

“…Interindividual variability in benzene biotransformation has also been related to genetic polymorphisms (Chen et al 2007;Hsieh et al 1999;Nebert et al 2002;Ross 2005;Sorensen et al 2003;Wan et al 2002). Glutathione conjugation catalysed by GST is a step in the metabolic pathway of benzene to SPMA and GSTT1 genotype was associated with excretion of SPMA, suggesting a key role of that enzyme in benzene metabolism.…”

“…Genetic polymorphisms of several benzene biotransformation enzymes (CYP2E1, EPHX1, GSTM1, GSTT1, GSTP1) have been associated with modulations in the urinary excretion rate of benzene metabolites and benzene toxicity (Chen et al 2007;Hsieh et al 1999;Nebert et al 2002;Qu et al 2005;Ross 2005;Sorensen et al 2003Sorensen et al , 2004Wan et al 2002).…”

Utilização de biomarcadores de genotoxicidade e expressão gênica na avaliação de trabalhadores de postos de combustíveis expostos a vapores de gasolina

“…Atualmente, existem diferentes métodos de identificação de polimorfismos envolvidos com a susceptibilidade à exposição a diferentes agentes tóxi-cos. Dentre as principais técnicas de detecção de polimorfismos destacam-se: a reação em cadeia da polimerase (PCR) e suas variações, como por exemplo, o PCR de Polimorfismo de Comprimento dos Fragmentos de Restrição (RFLP), o sequenciamento, o PCR em tempo real e cromatografia líquida desnaturante de alta performance (DHPLC) 85,86,[88][89][90][91][92][93][94][95] .…”

Relationships between metabolic and non-metabolic susceptibility factors in benzene toxicity

“…The combination of a rapid CYP2E1 phenotype and the NQO1 null genotype led to a 7.8 fold increased risk of benzene poisoning [54]. Subsequent studies have investigated the role of metabolic susceptibility factors in benzene poisoning and have confirmed a potential role for the NQO1*2 polymorphism in benzene poisoning [63-65]. Additional enzyme systems implicated in benzene poisoning included CYP2E1, GSTT1 and GSTM1 [63-65].…”