POSTTRANSCRIPTIONAL REGULATION OF HUMAN MICROSOMAL EPOXIDE HYDROLASE

Microsomal epoxide hydrolase (mEH) is a key biotransformation enzyme t hat is variably expressed in humans, Genetic polymorphisms in the mEH gene have been identified that result in amino acid substitutions in t he corresponding enzyme. Results of expression analyses of the mEH all elic variants in vitro suggest that the mutations do not affect the sp ecific activity of the mEH enzyme, but may alter post-transcriptional regulation of mEH,To identify potential post-transcriptional mechanism s that influence mEH expression, the translational efficiency, mRNA ha lf-life, and protein half-life of mEH allelic variants were determined . Constructs encoding each of the four mEH alleles were transcribed in vitro and translated, No differences were detected in the rate of pro tein synthesis among the variant transcripts, indicating that the prev iously characterized coding region polymorphisms do not appear to affe ct translational efficiency, mEH variant RNA half-lives were determine d in transfected COS-1 cells, but no differences in decay rates were a pparent among the polymorphic constructs, Half-lives of the polymorphi c mEH proteins were determined in transiently transfected COS-1 cells treated with the protein synthesis inhibitor cycloheximide, Calculated protein half-lives were: Y113/H139, 15,2 h; H113/H139, 10.7 h, Y113/H 139, 16.9 h and H113/R139, 16.0 h, The protein half-lives calculated f or the polymorphic variants exhibited the same rank order as mEH prote in and activity levels determined previously from expression experimen ts in vitro and therefore suggest that polymorphic amino acid substitu tion may result in altered protein stability. However, the differences noted were not statistically significant at. the P < 0.05 level, and therefore additional study is required to firmly establish causative r elationships, Pharmacogenetics 8: 157-167 (C) 1998 Lippincott-Raven Pu blishers.