Valproate
Stanley R. Resor, Henn Kutt in The Medical Treatment of Epilepsy, 2020
Compared to VPA, valpromide offers two minor advantages, but presents one major disadvantage. VPA plasma levels derived from valpromide tend to fluctuate less than those derived from the free acid or sodium salt (95), and valpromide appears to be more effective than VPA in the prevention of febrile seizures (96), however, because it is a potent inhibitor of liver microsomal epoxide hydrolase (at least 100 times as potent as VPA itself) (97), in patients taking CBZ it dramatically increases the levels of CBZ-epoxide (average increase > 300%; range 100 to >800%), causing symptoms such as dizziness and confusion in some patients (98) and possibly increasing the risk of fetal malformations (99). However, interactions associated with valpromide may not be limited just to patients taking CBZ. Inhibition of epoxide hydrolase may have broader implications because the enzyme is important for the detoxification of reactive epoxide metabolites of drugs and environmental pollutants which can be cytotoxic, mutagenic, and carcinogenic (100).
Gynecological Cancer—Ovarian, Endometrial, Cervical
Peter G. Shields in Cancer Risk Assessment, 2005
Epoxide hydrolases (EPHX) play an important role in both the activation and detoxification of exogenous chemicals such as polycyclic aromatic hydrocarbons, a carcinogen found in cigarette smoke. Microsomal epoxide hydrolase is one of many enzymes that are part of the epoxide hydrolase family and is strongly expressed in the human ovary (56). A number of genetic polymorphisms coding for the EPHX gene have been described. In 1994, Hassett et al. identified the Tyr113His polymorphism on the EPHX gene that is the result of a substitution of Histidine for Tyrosine at codon 113. Further, a 40% decrease in EPHX activity has been demonstrated in vitro DNA expression studies for the His113His allelic variant compared to the Tyr113His variant (57). Consistent with these laboratory findings, a greater than twofold increase in the risk of ovarian cancer was observed in a case–control study among women who were homozygous for this polymorphism (Tyr113Tyr) compared to those who were homozygous or heterozygous (56). A limitation of the study was the lack of information on other risk factors. In order to confirm these results further replication is required.
Xenobiotic Biotransformation
Robert G. Meeks, Steadman D. Harrison, Richard J. Bull in Hepatotoxicology, 2020
The enzyme is present in several tissues. One form is in close proximity to P450 in the endoplasmic reticulum, and this may reflect its role in detoxification of electrophilic epoxides generated by P450. Epoxide hydrolase activities are also present in the plasma membrane, golgi apparatus, nuclear membrane, mitochondria, and cytosol. Because of differences in immunogenicity, pH optimum, molecular weight, and 1,1,1-trichloropropene oxide inhibition, the cytosolic and microsomal enzymes are believed to be two distinct forms. Epoxides that are good substrates for the microsomal epoxide hydrolase appear to be poor substrates for cytosolic epoxide hydrolase and vice versa. For example, styrene oxide, a common substrate for determination of enzyme activity, is a poor substrate for the cytosolic enzyme. Therefore, low substrate activity of one form appears to be compensated by the other. There are no known specific inducers of epoxide hydrolases, but PB, 3-MC, PCN, Aroclor 12154, trans-stilbene oxide, lindane, antioxidants, alcohols, ketones, and imidazoles all induce the microsomal form of the enzyme. 1,1,1-Trichloropropene oxide and cyclohexene oxide are the prototype enzyme substrates. The cytosolic form has PB as the only known inducer. On the other hand, the nuclear and microsomal forms are immunologically similar but have dissimilar substrate specificities and inducibility. Species and sex differences are not particularly noteworthy. The mouse has low activity but responds to induction to a greater degree. The low activity of the enzyme in mice could not be related to the sensitivity of this species to hepatocarcinogenicity. The principal example of epoxide hydrolase participation in a bioactivation reaction is generation of reactive vicinal dihydrodiol-epoxides, the major ultimate carcinogens of PAH.
Association between EPHX1 polymorphism rs1051740 and the risk of ovarian cancer: a meta-analysis
Published in Artificial Cells, Nanomedicine, and Biotechnology, 2019
Ying Jin
Epoxide hydrolase 1 (EPHX1) is an important phase II biotransformation enzyme in vivo, and plays a significant role in the activation and detoxification of toxins [10]. Generally, epoxides are regarded as the most toxicologically active form of drugs or environmental chemicals [11], while EPHX1 can promote the hydrolysis of epoxides into trans-dihydrodiols [12]. EPHX1 gene, coding for this enzyme, is located at chromosome 1q42.1 with 20271 base-pairs, and is composed of 9 exons and 8 introns [13]. In this gene, more than 10 single nucleotide polymorphisms (SNPs) have been identified. Among them, the polymorphism rs1051740 leading to the substitution of tyrosine to histidine at exon 3 has been reported to reduce the enzyme activity by more than 40% in vitro [14]. Considering the role of EPHX1 in response to exogenous toxins, this polymorphism of the gene EPHX1 has been proposed to be related to the risk of multiple cancers, including ovarian cancer [15], hepatocellular carcinoma [13] and colorectal cancer [14].
Inhibition of soluble epoxide hydrolase by phytochemical constituents of the root bark of Ulmus davidiana var. japonica
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2021
Jang Hoon Kim, Ji Su Park, Yun Ji Lee, Sena Choi, Young Ho Kim, Seo Young Yang
Soluble epoxide hydrolase (sEH, E.C. 3.3.2.10) is a member of the α/β hydrolase family found in both the cytosolic and peroxisomal compartments of the cell. sEH is composed of two independently folding domains within the C-terminal and N-terminal1. The C-terminal domain has epoxide hydrolase activity that converts epoxyeicosatrienoic acids (EETs) into dihydroxyeicosatrienoic acids (DHETs), while the N-terminal domain has a phosphatase activity that hydrolases lipid phosphates2. EETs derived from arachidonic acid exist in four regioisomers distinguished by the location of epoxide, denoted 5,6-EET, 8,9-EET, 11,12-EET, and 14,15-EET3. EETs are secreted into vascular endothelial and renal epithelial cells, where they contribute to amelioration of hypertension and chronic kidney disease as endothelial-derived hyperpolarising factors, and by inhibiting epithelial sodium channels in the kidney4.
Predictive role of polymorphic variants of phase II drug metabolising enzyme in modulating toxicity in North Indian lung cancer patients undergoing chemotherapy
Published in Xenobiotica, 2022
Harleen Walia, Parul Sharma, Navneet Singh, Siddharth Sharma
Microsomal epoxide hydrolase (EPHX1) is a Phase II enzyme that is involved in the general oxidative protection against a myriad of substances in the environment but is also primarily responsible for the xenobiotic activation of tobacco smoke carcinogens (Gresner et al. 2007). In the EPHX1 coding region, two specific polymorphisms are characterised in exon 3 and 4 and studied extensively In exon 3, Tyr113His (rs2854455) results in a T to C substitution whereas, in exon4, His139Arg (rs2234922) results in A to G substitution, and both of these polymorphic variants have been found to modulate the enzyme activity. The His113His allele has been to be associated with at least 50% (slow allele) of reduced enzyme activity whereas, and the Arg139Arg allele increased the enzyme activity by 25% (short allele) (Yu et al. 2015).