Association between metabolic gene polymorphisms and susceptibility to peripheral nerve damage in workers exposed ton-hexane: A preliminary study

Abstract

Chronic exposure to n-hexane may result in peripheral neuropathy. 2,5-Hexanedione (2,5-HD) has been identified as a toxic metabolite of n-hexane. The CYP2E1, CYP1A1 and GST genes are involved in the formation of 2,5-hexanedione from n-hexane as well as the elimination of 2,5-HD-formed electrophile, and these genes are highly polymorphic in the general population. A nested case-control study in an industrial cohort was conducted to evaluate the associations between polymorphisms in these metabolic genes and n-hexane-induced peripheral nerve damage. The study subjects included 22 cases, who worked in a printing factory with symptoms of peripheral nerve damage, and 163 controls, who came from the same factory of cases. DNA was extracted from blood samples and genotyping was conducted for CYP2E1 Pst, CYP2E1 Dra, CYP2E1 Ins96, CYP1A1 Msp, GSTT1 null, GSTM1 null and GSTP1 105V. Unconditional logistic regression was applied to estimate the odds ratio and 95% confidence intervals. There were no significant differences between the two groups regarding age, sex, smoking and alcohol status. A significant association between Dra polymorphism and peripheral nerve damage was found. The frequency of CYP2E1 Dra homozygous mutation in the case group (18.2%) was higher than that in the control group (3.7%, p=0.015). Individuals with homozygote genotype (CC) of CYP2E1 Dra had a significantly higher risk of peripheral nerve damage compared with those with DD genotype (adjusted OR=?.58, 95% CI=1.32-23.65) after n-hexane exposure duration, sex, age, smoking and alcohol status were adjusted. No significant association was found that CYP2E1 Pst, CYP2E1 Ins96, CYP1A1 Msp, GSTT1, GSTM1, GSTP gene polymorphisms associated with the susceptibility of peripheral nerve damage. These findings suggested that CYP2E1 gene might increase the susceptibility to n-hexane-induced peripheral damage.

Neurotoxic effect of 2,5-hexanedione on neural progenitor cells and hippocampal neurogenesis

“…Occupational or intentional exposure to n-hexane via inhalation or skin absorption in abuse scenarios is linked to neuropathy (Huang, 2008). n-Hexane metabolism is principally mediated by the cytochrome P450 enzyme CYP2E1; CYP2E1-mediated n-hexane metabolism can result in free radical formation (Jenner, 1998) and is implicated in n-hexane-induced peripheral neuropathy in humans (Zhang et al, 2006). The major metabolites of n-hexane are 2-hexanol, methyl n-butyl ketone, 4,5-dihydroxy-2-hexanone, and 2,5-hexanedione (HD) (Nakajima et al, 1991).…”

Independent and Combined Effects of Ethanol Self-Administration and Nicotine Treatment on Hepatic CYP2E1 in African Green Monkeys

“…Several polymorphisms have been identified in the human CYP2E1 gene. Individuals with the CYP2E1 RsaI c2 allele, associated with increased CYP2E1 transcriptional activity (Hayashi et al, 1991), are more susceptible to toxicity from industrial chemicals bioactivated by CYP2E1 such as vinyl chloride (Wang et al, 2010) and n-hexane (Zhang et al, 2006). This and other CYP2E1 genetic variants have been associated with increased risk for hepatocellular (Munaka et al, 2003), colorectal (Morita et al, 2009), and esophageal cancer (Liu et al, 2007).…”

Polymorphisms of GSTT1, GSTM1, and EPHX genotypes in patients with cryptogenic polyneuropathy: a case–control study

“…Impaired breakdown of PAHs in persons with the null genotype of GSTs may lead to increased exposure on nerves and thereby increased loss of nerves. n‐Hexane is another toxic substance that is present in cigarette smoke and is well known to cause polyneuropathy (Zhang et al 2006). However, in our study, smoking did not increase the risk of polyneuropathy.…”