Epoxide hydrolase 1 is an
enzyme
Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products ...
encoded by the ''EPHX1''
gene
In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...
in humans.
Function
Epoxide hydrolase
Epoxide hydrolases (EH's), also known as epoxide hydratases, are enzymes that metabolize compounds that contain an epoxide residue; they convert this residue to two hydroxyl residues through an epoxide hydrolysis reaction to form diol products. ...
plays an important role in both the activation and detoxification of exogenous chemicals such as
polycyclic aromatic hydrocarbon
A polycyclic aromatic hydrocarbon (PAH) is a class of organic compounds that is composed of multiple aromatic rings. The simplest representative is naphthalene, having two aromatic rings and the three-ring compounds anthracene and phenanthrene. ...
s.
Discovery
Microsomal epoxide hydrolase 1 (EPHX1) was first isolated by Watabe and Kanehira from rabbit liver and later also purified from human liver and characterized. EPHX1 belongs to the family of α/β hydrolases and converts epoxides to diols.
Tissue distribution
EPHX1 protein can be found predominantly in the membrane fraction of the
endoplasmic reticulum of
eucaryotic cells. Its expression in mammals is generally the highest in the liver, followed by
adrenal gland
The adrenal glands (also known as suprarenal glands) are endocrine glands that produce a variety of hormones including adrenaline and the steroids aldosterone and cortisol. They are found above the kidneys. Each gland has an outer cortex whic ...
, lung, kidney, and intestine. It was found also in bronchial
epithelial
Epithelium or epithelial tissue is one of the four basic types of animal tissue, along with connective tissue, muscle tissue and nervous tissue. It is a thin, continuous, protective layer of compactly packed cells with a little intercell ...
cells and upper gastrointestinal tract. EPHX1 expression is individually variable among humans and it can be modestly induced by chemicals as phenobarbital, β-naphtoflavone, benzanthracene, trans-stilbene oxide, etc.
Gene structure and ontology
Human EPHX1
orthologues were found in 127 organisms. Human
microsomal
In cell biology, microsomes are heterogeneous vesicle-like artifacts (~20-200 nm diameter) re-formed from pieces of the endoplasmic reticulum (ER) when eukaryotic cells are broken-up in the laboratory; microsomes are not present in healthy, liv ...
epoxide hydrolase is coded by EPHX1 gene located on chromosome 1 (1q42.12). Three transcription variants differing in the
5´-untranslated region have been identified with length of 455 amino acids.
Function
Conversion of
epoxide
In organic chemistry, an epoxide is a cyclic ether () with a three-atom ring. This ring approximates an equilateral triangle, which makes it strained, and hence highly reactive, more so than other ethers. They are produced on a large scale ...
s to trans-dihydrodiols presents prototypical EPHX1 reaction.
EPHX1 has broad substrate specificity. EPHX1 detoxifies low molecular weight chemicals, e.g., butadiene, benzene, styrene, etc., but more complex compounds as polycyclic aromatic hydrocarbons are rather bioactivated to genotoxic species.
EPHX1 mediates the sodium-dependent transport of
bile acids into
hepatocyte
A hepatocyte is a cell of the main parenchymal tissue of the liver. Hepatocytes make up 80% of the liver's mass.
These cells are involved in:
* Protein synthesis
* Protein storage
* Transformation of carbohydrates
* Synthesis of cholesterol, ...
s. Androstene oxide and epoxyestratrienol have been shown as endogenous EPHX1 substrates. EPHX1 also metabolizes
endocannabinoid
Cannabinoids () are several structural classes of compounds found in the cannabis plant primarily and most animal organisms (although insects lack such receptors) or as synthetic compounds. The most notable cannabinoid is the phytocannabinoid tet ...
2-arachidonoylglycerol to
arachidonic acid and may play an important role in the endocannabinoid signaling pathway.
Clinical significance
Mutations in EPHX1 have been linked with
preeclampsia
Pre-eclampsia is a disorder of pregnancy characterized by the onset of high blood pressure and often a significant amount of protein in the urine. When it arises, the condition begins after 20 weeks of pregnancy. In severe cases of the disease ...
, elevated blood levels of
bile salts
Bile acids are steroid acids found predominantly in the bile of mammals and other vertebrates. Diverse bile acids are synthesized in the liver. Bile acids are conjugated with taurine or glycine residues to give anions called bile salts.
Primary b ...
(i.e. hypercholanemia),
Fetal hydantoin syndrome
Fetal hydantoin syndrome, also called fetal dilantin syndrome, is a group of defects caused to the developing fetus by exposure to teratogenic effects of phenytoin. Dilantin is the brand name of the drug phenytoin sodium in the United States, com ...
, and
diphenylhydantoin toxicity. Functional
single nucleotide polymorphisms (SNPs) in EPHX1 have been found and frequently studied. Two SNPs - Y113H (rs1051740, T337C) and H139R (rs2234922, A416G) – seemed to influence EPHX1 activity in vitro and their combination was used for deduction of EPHX1 activity. However, their functional effect was not confirmed in human liver microsomes.
Due to the EPHX1 role in metabolism of procarcinogens and existence of gene variations with functional effect a number of association studies has been conducted. Significant associations between EPHX1 SNPs and risk of lung, upper aerodigestive tract, breast, and ovarian cancers have been observed in various populations. Meta-analyses confirmed associations of rs1051740 and rs2234922 SNPs with the risk of lung cancer. Meta-analyses reporting no association of these SNPs with esophageal and hepatocellular cancer risk have been reported as well ). Genetically predicted low EPHX1 activity was associated with increased risk of developing tobacco-related cancer in smokers from 47089 Danish individuals .
Recent meta-analysis comprising 8,259 patients with chronic obstructive pulmonary disease (COPD) and 42,883 controls reported that the predicted slow activity EPHX1 phenotype is a significant risk factor for
COPD
Chronic obstructive pulmonary disease (COPD) is a type of progressive lung disease characterized by long-term respiratory symptoms and airflow limitation. The main symptoms include shortness of breath and a cough, which may or may not produce ...
in Caucasian, but not in Asian population. Role of EPHX1 expression in pathogenesis of neurodegeneration as Alzheimer´s disease, methamphetamine-induced drug dependence, and cerebral metabolism of epoxyeicosatrienoic acids
was suggested. Modulation of metabolism of epoxyeicosatrienoic acids by EPHX1 may interfere with, e.g., signal transmission of neurons, vasodilation, cardiovascular homeostasis, and inflammation. Transformation of the current knowledge about EPHX1 into clinical applications is, however, limited by the lack of crystal structure of the enzyme and by the complex relations between its genotype and phenotype.
Notes
References
Further reading
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