TY - JOUR
T1 - Human hepatic microsomal epoxide hydrolase
T2 - Comparative analysis of polymorphic expression
AU - Hassett, Christopher
AU - Lin, Jing
AU - Carty, Cara L.
AU - Laurenzana, Elizabeth M.
AU - Omiecinski, Curtis J.
N1 - Funding Information:
We thank Dr. Kenneth Thummel and Ms. Susan Hurst of the Department of Pharmaceutics for access to the human liver samples. We also thank the NIEHS Center for Ecogenetics Molecular Biomarker Laboratory for assistance with DNA genotyping assays. This research was supported by the following grants from the NIH: ES-04978 (C.J.O.), ES-07032 (E.M.L.), and Center Grant ES-07033. C.J.O. is a Burroughs Wellcome Fund Toxicology Scholar.
PY - 1997/1/15
Y1 - 1997/1/15
N2 - 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.
AB - 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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U2 - 10.1006/abbi.1996.9794
DO - 10.1006/abbi.1996.9794
M3 - Article
C2 - 9016823
AN - SCOPUS:0031568236
SN - 0003-9861
VL - 337
SP - 275
EP - 283
JO - Archives of Biochemistry and Biophysics
JF - Archives of Biochemistry and Biophysics
IS - 2
ER -