Polymorphisms in phase I and phase II metabolism genes and risk of chronic benzene poisoning in a Chinese occupational population

Abstract

It is widely accepted that the cytotoxicity and genotoxicity of benzene results from the action of reactive metabolites. Therefore, genetic variation in metabolic enzyme genes may contribute to susceptibility to chronic benzene poisoning (CBP) in the exposed population. Using a case-control study that included 268 benzene-poisoned patients and 268 workers occupationally exposed to benzene in South China, we aimed to investigate the association between single-nucleotide polymorphisms in genes with phase I and II of metabolism and risk of CBP. The TaqMan technique was used to detect polymorphisms of CYP1A1, CYP1A2, CYP1B1, ADH1B, EPHX1, EPHX2, NQO1, MPO, GSTP1 and UGT1A6 genes. We also explored potential interactions of these polymorphisms with lifestyle factors such as cigarette smoking and alcohol consumption. A weak positive association was found between glutathione S-transferase pi-1 (GSTP1) rs1695 polymorphism and the risk of CBP (P = 0.046), but this association was not statistically significant (P = 0.117) after adjustment for potential confounders. Further analysis showed that the risk of CBP increased in the subjects with EPHX1 GGAC/GAGT diplotype (P = 0.00057) or AGAC/GAGT diplotype (P = 0.00086). In addition, we found that alcohol drinkers with the EPHX1 rs3738047 GA + AA genotypes and non-alcohol drinkers with the GSTP1 rs1695 AA genotype tended to be more susceptible to benzene toxicity. Our results suggest that genetic polymorphisms in EPHX1 may contribute to risk of CBP in a Chinese occupational population.

Are polymorphisms in metabolism protective or a risk for reduced white blood cell counts in a Chinese population with low occupational benzene exposures?

“…31 Previous studies have shown that individuals vary in their susceptibility to the adverse effects of benzene, probably due to differences in metabolic genes and corresponding enzymatic activity. 12,32 It is postulated Table 5 The effect of cumulative exposure dose (CED) and metabolic enzymes genes in a multiplicative model among benzene-exposed workers SNP, single nucleotide polymorphism. a The exposed workers were divided into four groups with quarter cumulative exposure dose (CED).…”

“…Genetic polymorphisms in genes encoding CYP2E1, mEH, and GSTs may account for human variable responses to benzene because they affect the level of expression, structure, or catalytic activity of these metabolic enzymes. 12 Genetic predisposition (polymorphisms) to benzene toxicity is currently under investigation. [13][14][15] Previous studies have explored the relationship between genetic polymorphisms and benzene metabolism on the premise of high exposure, or without precise measurements of air exposure, or with small numbers of participants.…”

Avaliação citogenética e molecular de trabalhadores intoxicados pelo benzeno

“…Assim como, a detoxificação das quinonas pode ocorrer via NQO1 ou via enzimas da fase II de metabolização de xenobióticos como as GSTs, resultando em produtos menos tóxicos como as diidroquinonas (Ross et al, 2000). Outras enzimas de metabolização, incluindo CYP1A1, CYP1A2, CYP1B1 e epóxido hidrolase solúvel (sEH; EPHX2), podem converter o benzeno e seus metabólitos, no fígado, em outros metabólitos intermediários, que também podem contribuir para a toxicidade do benzeno (Sun et al, 2008 polimorfismo CYP2E1 e genótipo GSTT1 nulo (Wan et al, 2002). Esses resultados em relação ao NQO1 não foram confirmados em trabalho semelhante, também realizado na China (Sun et al, 2008).…”

“…Outras enzimas de metabolização, incluindo CYP1A1, CYP1A2, CYP1B1 e epóxido hidrolase solúvel (sEH; EPHX2), podem converter o benzeno e seus metabólitos, no fígado, em outros metabólitos intermediários, que também podem contribuir para a toxicidade do benzeno (Sun et al, 2008 polimorfismo CYP2E1 e genótipo GSTT1 nulo (Wan et al, 2002). Esses resultados em relação ao NQO1 não foram confirmados em trabalho semelhante, também realizado na China (Sun et al, 2008). Entretanto, Chen e colaboradores (2007) Itália, não só em relação ao GSTT1 nulo como também ao GSTM1 nulo.…”

“…Na presente investigação, não foram encontradas diferenças entre os grupos avaliados. Esse achado corrobora com dados encontrados em outros estudos (Wan et al, 2002;Kim et al, 2008;Sun et al,2008).…”