DEVELOPMENTAL EXPRESSION OF HUMAN MICROSOMAL EPOXIDE HYDROLASE

Microsomal epoxide hydrolase (mEH) is a critical biotransformation enz yme that catalyzes the hydrolysis of a large number of epoxide interme diates, which arise frequently from the oxidation of pharmaceutical an d environmental compounds by the cytochrome P450 mixed function oxygen ase system. The enzyme mEH has been implicated directly as a key deter minant of certain chemically initiated cancers and developmental toxic ities. To evaluate mEH expression in human tissues and provide a frame work for assessing the relative risk in the fetus to potential develop mental toxins, in the current study, the authors characterized mEH in human tissues as a function of gestational age. Analyses included enzy matic activity determinations, immunochemical quantitation of protein levels and RNA hybridization assays. With respect to activity, hepatic mEH enzymatic levels were strongly correlated with increasing gestati onal age (r =.82, P <.001). Similarly, mEH activity levels in the live r were highly correlated with protein contents (r =.93, P <.001). Howe ver, mEH enzymatic activity in the fetal lung did not exhibit similar concordance nor did measured RNA levels appear to correlate with enzym atic activity levels in fetal or adult tissue samples. Of the fetal ti ssues surveyed, the liver and adrenal glands exhibited the highest lev els of detectable mEH RNA, followed by the lung and kidney. These data suggest that post-transcriptional regulatory pathways may be importan t in determining constitutive levels of mEH functional activity and th at fetuses during early gestation may be uniquely sensitive to the pre sentation of epoxide-containing xenobiotics compared with fetuses at l ater stages of development.