Variability in human sensitivity to 1,3‐butadiene: Influence of the allelic variants of the microsomal epoxide hydrolase gene

Abstract

The carcinogenic effects of 1,3-butadiene (BD), a chemical widely used in the rubber industry, are thought to be due to its epoxide metabolites. In humans, these epoxides are detoxified predominantly by hydrolysis, a reaction mediated by the microsomal epoxide hydrolase (mEH) enzyme. The mEH gene is polymorphic and the most common mEH coding-region variants detected in human populations are the two amino acid polymorphisms Tyr113His and His139Arg. Polymorphic amino acid substitutions at residues 113 and 139 in the human mEH protein can associate in four distinct combinations: Tyr113/His139, Tyr113/Arg139, His113/His139, and His113/Arg139. In vitro studies have shown that each of these genotypes has a unique mEH protein level that can affect net mEH enzymatic activity. In the current study, we examined the relationships among the genotypes involving these two polymorphisms and the mutagenic responses associated with occupational exposure to BD. We studied 49 nonsmoking workers from two styrene-butadiene rubber facilities in southeast Texas using the autoradiographic HPRT mutant lymphocyte assay as a biomarker of genotoxic effect. We genotyped the study participants simultaneously for both polymorphisms, using a multiplex PCR assay developed in our laboratory, and the subjects were assigned to a specific group based on the predicted mEH activity associated with their genotypes (low, intermediate, and high). In the study population, 67% were exposed to low BD levels of <150 ppb (measured by personal badge dosimeters) and 33% were exposed to >150 ppb (mean 2,244 ppb). In the BD low-exposure group, the mEH genotypes had no significant effect on the HPRT variant (mutant) frequency (Vf). In the high-exposure group (BD > 150 ppb), individuals with genotypes associated with low mEH activity had a significant (P < 0.05) 3-fold increase in HPRT Vf (Vf +/- SEM = 13.95 +/- 2.15 x 10(-6)) compared to high-activity individuals (4.41 +/- 1.19 x 10(-6)), and a 2-fold increase in Vf compared to intermediate-activity individuals (6.44 +/- 2.09 x 10(-6)). Our results indicate that mEH genotypes may play a significant role in human sensitivity to the genotoxic effects of exposure to BD.

Lack of increased genetic damage in 1,3-butadiene-exposed Chinese workers studied in relation to EPHX1 and GST genotypes

“…In the present study, we examined this Y113H polymorphism in EPHX1 as well as another functional polymorphic variant at position 139 (H139R), so as to provide a more complete phenotypic picture of this important enzyme in BD metabolism. Abdel-Rahman et al have also recently performed a similar analysis in their study and have presented findings that support their earlier conclusion that EPHX1 polymorphisms influence BD genotoxicity in humans [30]. They reported that EPHX1 polymorphisms that are predicted to confer low EPHX1 activity elevated the HPRT variant frequency in workers exposed to >150 ppb BD by two-to three-fold in comparison to that found in workers with intermediate to high EPHX1 activity.…”

“…In contrast, we found no effect of either genetic polymorphisms in EPHX1 or predicted EPHX1 activity on HPRT gene mutant frequency following BD exposure. The reasons for this difference are unclear, but the recent findings of Abdel-Rahman et al [30] are based on a comparison of only seven BD-exposed workers with low EPHX1 activities against nine with intermediate to high activity. Our negative findings are based upon a larger population comparing 27 BD-exposed workers with low activity against 12 with intermediate to high EPHX1 activity.…”

The association between genetic damage in peripheral blood lymphocytes and polymorphisms of three glutathione S-transferases in Chinese workers exposed to 1,3-butadiene

“…The results obtained from examination of BD-exposed populations suggest that polymorphisms in GSTs might modulate the levels of DNA damage associated with BD exposure. It has been reported that SCE, CA, and MN frequencies were increased following DEB exposure in human lymphocytes carrying the GSTT1 (−) genotype; it was also found that the frequency of SCE was elevated in lymphocytes carrying the GSTM1 (−) genotype, which had been exposed to EB [33][34][35][36]. The GSTT1 gene has recently been identified as a possible biomarker of susceptibility to BD and its metabolites.…”

Evaluation of Cancer Tests of 1,3-Butadiene Using Internal Dose, Genotoxic Potency, and a Multiplicative Risk Model

“…There are, however, other studies in humans showing a significant difference in levels of mutations and cytogenetic effects related to BD exposures (e.g., refs. 45,46). The large species difference in sensitivity to BD observed in the rodent cancer tests are according to the evaluation due to a difference in the metabolism to DEB.…”