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Human Hepatic Microsomal Epoxide Hydrolase: Comparative Analysis of Polymorphic Expression

https://doi.org/10.1006/abbi.1996.9794Get rights and content

Abstract

Interindividual variation in the expression of human microsomal epoxide hydrolase (mEH) may be an important risk factor for chemically induced toxicities, including cancer and teratogenesis. In this study, phenotypic variability and mEH genetic polymorphisms were examined in a bank of 40 transplant-quality human liver samples. Immunochemically determined protein content, enzymatic activities, polymorphic amino acids, as well as mEH RNA levels were evaluated in parallel. Enzymatic activity was assessed using (±)-benzo[a]pyrene-4,5-epoxide at 2 substrate concentrations. The relative hydrolyzing activities obtained using saturating substrate levels were highly correlated (r= 0.85) with results derived from limiting substrate concentrations and exhibit approximately an 8-fold range in activity levels across the panel of 40 liver samples. mEH enzyme activity also demonstrated strong correlation (r≥ 0.74) with an 8.4-fold variation determined for mEH protein content within the same samples. However, these protein/activity measurements were poorly correlated (r≤ 0.23) with mEH RNA levels, which exhibited a 49-fold variation. Two common polymorphic amino acid loci in the mEH protein did not exclusively account for variation in enzymatic activity, although this conclusion is confounded by heterozygousity in the samples. These data demonstrate the extent of hepatic mEH functional variability in well-preserved human tissues and suggest that polymorphism of mEH protein expression is regulated in part by posttranscriptional controls, which may include nonstructural regulatory regions of the mEH transcript.

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    The EPHX1 gene encoding mEH enzyme is also highly polymorphic. The two common variants, c.337T>C (rs1051740) and c.416A>G (rs2234922), have been demonstrated to change the catalytic activity of mEH both in vitro and in vivo (Hassett et al., 1994, 1997; Kitteringham et al., 1996; Nakajima et al., 2005). Patients with the variant c.337T>C or c.416A>G allele tended to have higher CBZ doses or lower CBZ concentration–dose ratios (CDRs) (Makmor-Bakry et al., 2009; Hung et al., 2012).

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Supported by NIH Grant ES-04978 to C.J.O.

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