Tissue-specific expression and alternative splicing of human microsomal epoxide hydrolase

Human microsomal epoxide hydrolase (HYL1) plays an important role in the detoxification of environmental compounds and drugs, such as the aromatic anticonvulsants phenytoin, carbamazepine, and phenobarbital, by converting their P450-generated epoxide metabolites into nontoxic diols, Recently, we have shown that a genetic defect altering the structure and function of the HYL1 protein is unlikely to be responsible for predisposing individuals to idiosyncratic hypersensitivity reactions from anticonvulsants. To evaluate the possible involvement of regulatory mechanisms, we used 5' rapid amplification of cDNA ends (RACE) and reverse transcription polymerase chain reaction (RT-PCR) to identify and characterize HYL1 5' cDNA ends, In addition to exon 1 (El) previously isolated from a liver cDNA library, we isolated four new exons (El-a, El-c, E1-d, and El-e) from various tissues, El was always directly connected to exon 2 (E2) where the translation start codon is located, El-a, El-c E1-d, and El-e are alternatively spliced to E2, having either El-a or E1-a' (a truncated form of El-a) at the 5' end of their respective transcript, Genomic data indicate that exons Ela and El-c are located at least 7 kb upstream from El, Furthermore, we demonstrated a tissue-specific expression pattern for El-containing mRNA species, whereas El-a-containing transcripts appear to be expressed ubiquitously, Our results provide evidence that microsomal epoxide hydrolase is regulated by multiple untranslated exons flanked by tissue-specific promoters.