Journal article
The Expression of Human Microsomal Epoxide Hydrolase Is Predominantly Driven by a Genetically Polymorphic Far Upstream Promoter
The Journal of pharmacology and experimental therapeutics, Vol.330(1), pp.23-30
07/2009
Handle:
https://hdl.handle.net/2376/107468
PMCID: PMC2700158
PMID: 19364907
Abstract
Microsomal epoxide hydrolase (EPHX1) biotransforms epoxide derivatives of
pharmaceuticals, including metabolites of certain antiepileptic medications,
such as phenytoin and carbamazepine, and many environmental epoxides, such as
those derived from butadiene, benzene, and carcinogenic polyaromatic
hydrocarbons. We previously identified a far upstream promoter region,
designated E1-b, in the EPHX1 gene that directs expression of an alternatively
spliced EPHX1 mRNA transcript in human tissues. In this investigation, we
characterized the structural features and expression character of the E1-b
promoter region. Results of quantitative real-time polymerase chain reaction
analyses demonstrated that the E1-b variant transcript is preferentially and
broadly expressed in most tissues, such that it accounts for the majority of
total EPHX1 transcript in vivo. Comparative genomic sequence comparisons
indicated that the human EPHX1 E1-b gene regulatory region is
primate-specific. Direct sequencing and genotyping approaches in 450
individuals demonstrated that the E1-b promoter region harbors a series of
transposable element cassettes, including a polymorphic double Alu insertion.
Results of reporter assays conducted in several human cell lines demonstrated
that the inclusion of the Alu(+/+) insertion significantly decreases basal
transcriptional activities. Furthermore, using haplotype block analyses, we
determined that the E1-b polymorphic promoter region was not in linkage
disequilibrium with two previously identified nonsynonomous single nucleotide
polymorphisms (SNPs) in the coding region or with functional SNPs previously
identified in the proximal promoter region of the gene. These results
demonstrate that the upstream E1-b promoter is the major regulator of EPHX1
expression in human tissues and that polymorphism in this region may
contribute an interindividual risk determinant to xenobiotic-induced
toxicities.
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Details
- Title
- The Expression of Human Microsomal Epoxide Hydrolase Is Predominantly Driven by a Genetically Polymorphic Far Upstream Promoter
- Creators
- Xi Yang - Center for Molecular Toxicology and Carcinogenesis, Department of Veterinary and Biomedical Sciences, Pennsylvania State University, University Park, Pennsylvania (X.Y., S.-H.L., D.M.W., C.J.O.); and Departments of Pharmacology and Health Evaluation Sciences, Pennsylvania State University College of Medicine, Hershey, Pennsylvania (P.L., C.J.G.)Shun-Hsin Liang - Center for Molecular Toxicology and Carcinogenesis, Department of Veterinary and Biomedical Sciences, Pennsylvania State University, University Park, Pennsylvania (X.Y., S.-H.L., D.M.W., C.J.O.); and Departments of Pharmacology and Health Evaluation Sciences, Pennsylvania State University College of Medicine, Hershey, Pennsylvania (P.L., C.J.G.)Denise M Weyant - Center for Molecular Toxicology and Carcinogenesis, Department of Veterinary and Biomedical Sciences, Pennsylvania State University, University Park, Pennsylvania (X.Y., S.-H.L., D.M.W., C.J.O.); and Departments of Pharmacology and Health Evaluation Sciences, Pennsylvania State University College of Medicine, Hershey, Pennsylvania (P.L., C.J.G.)Philip Lazarus - Center for Molecular Toxicology and Carcinogenesis, Department of Veterinary and Biomedical Sciences, Pennsylvania State University, University Park, Pennsylvania (X.Y., S.-H.L., D.M.W., C.J.O.); and Departments of Pharmacology and Health Evaluation Sciences, Pennsylvania State University College of Medicine, Hershey, Pennsylvania (P.L., C.J.G.)Carla J Gallagher - Center for Molecular Toxicology and Carcinogenesis, Department of Veterinary and Biomedical Sciences, Pennsylvania State University, University Park, Pennsylvania (X.Y., S.-H.L., D.M.W., C.J.O.); and Departments of Pharmacology and Health Evaluation Sciences, Pennsylvania State University College of Medicine, Hershey, Pennsylvania (P.L., C.J.G.)Curtis J Omiecinski - Center for Molecular Toxicology and Carcinogenesis, Department of Veterinary and Biomedical Sciences, Pennsylvania State University, University Park, Pennsylvania (X.Y., S.-H.L., D.M.W., C.J.O.); and Departments of Pharmacology and Health Evaluation Sciences, Pennsylvania State University College of Medicine, Hershey, Pennsylvania (P.L., C.J.G.)
- Publication Details
- The Journal of pharmacology and experimental therapeutics, Vol.330(1), pp.23-30
- Academic Unit
- Pharmaceutical Sciences, Department of
- Publisher
- American Society for Pharmacology and Experimental Therapeutics
- Identifiers
- 99900547373801842
- Language
- English
- Resource Type
- Journal article