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Renal Drug-Metabolizing Enzymes in Experimental Animals and Humans
Published in Robin S. Goldstein, Mechanisms of Injury in Renal Disease and Toxicity, 2020
Epoxide hydrolases are enzymes that catalyze the conversion of epoxides to dihydrodiols, thus preventing or reducing their reaction with cellular target macromolecules (protein and/or DNA). Three forms of epoxide hydrolase have been identified in the liver, one in the cytosol and two membrane-associated forms. The enzyme in the cytosol fraction catalyzes the hydration of several alkene oxides (e.g., trans-stilbene oxide, styrene oxide) and is inducible by clofibrate and nafenopin (Hammock and Ota, 1983; Waechter et al., 1988). Of the two known microsomal forms, one catalyzes the conversion of cholesterol-5,6-oxide to the corresponding diol and displays no activity towards xenobiotic epoxides (Oesch et al., 1984). The second and major microsomal form is responsible for the hydration of a wide variety of xenobiotic arene and alkene oxides (e.g., benzo(a)pyrene 4–5 oxide, styrene oxide) (Oesch et al., 1971). This enzyme is both immunologically and enzymatically distinct from the cholesterol-5, 6-epoxide hydrolase and the cytosolic form. The xenobiotic-metabolizing form of epoxide hydrolase is localized to the nuclear membrane (Gonzalez and Kasper, 1982) and is found in association with the cytochrome P-450 mixed-function oxidase system, which catalyzes the oxidation of both endogeneous and xenobiotic compounds to electrophilic epoxides (see the section titled Cytochromes P-450).
Valproate
Published in Stanley R. Resor, Henn Kutt, The Medical Treatment of Epilepsy, 2020
J. Christine Dean, J. Kiffin Penry
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).
Antiepileptic Drug Interactions: An Overview
Published in Carl L. Faingold, Gerhard H. Fromm, Drugs for Control of Epilepsy:, 2019
Valproic acid is an inhibitor of epoxide hydrolase and its use with carbamazepine may lead to higher than expected concentrations of CBX-epoxide.32,33 In addition, phenytoin stimulates the conversion of carbamazepine to CBZ-epoxide, and thus treatment of a patient with phenytoin, carbamazepine, and valproate can lead to unexpectedly low carbamazepine concentrations but excessively high concentrations of CBZ-epoxide.
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).
Peroxisome proliferator-activated receptor-gamma (PPARγ) and its immunomodulation function: current understanding and future therapeutic implications
Published in Expert Review of Clinical Pharmacology, 2022
Carlos Antonio Trindade da Silva, Juliana Trindade Clemente-Napimoga, Henrique Ballassini Abdalla, Rosanna Tarkany Basting, Marcelo Henrique Napimoga
Additionally, we suggest the crosstalk between 15d-PGJ2 and soluble epoxide hydrolases (sEH). Specifically, the inhibition of the sEH enzyme results in increased levels of other bioactive lipids mediators like EETs and other epoxy-fatty acids with anti-inflammatory and analgesic properties. EETs revealed to be a natural agonist of PPARy, opening new avenues to exploring new pharmacological strategies, like sEH inhibitors. Particularly, significant advances have been achieved in the last years with the development of sEH inhibitors. The FDA has recently approved sEH inhibitors in clinical trials, supporting new perspectives for pain control and resolution of inflammation. From a translation perspective, bioactive lipids mediators like EETs could be helpful when exogenous administrated. However, EETs are rapidly metabolized into their inactive diols by the sEH. For that, the use of the sEH inhibitors can enhance the bioavailability of these lipids, improving their analgesic and resolutions actions. Also, SPMs demonstrate potent anti-inflammatory activity partially dependent on a PPARγ mechanism, corroborating the concept that these bioactive lipids mediators interact (in fully or partially dependency) with PPARγ.
Omega‐3 Polyunsaturated Fatty Acids and Lung Cancer: nutrition or Pharmacology?
Published in Nutrition and Cancer, 2021
Owen M. Vega, Shaheen Abkenari, Zhen Tong, Austin Tedman, Sara Huerta-Yepez
In addition, to the COX pathway, ω-3 and ω-6 PUFAs are substrates of multiple pathways including the LOX and cytochrome P450 epoxygenases (96, 97). CYP epoxygenase produce epoxyeicosatrienoic acids (EETs) through the ω-6 PUFA, AA. These enzymes also produce epoxy docosapentaenoic acids (EDPs) through the ω-3 PUFA, DHA. AA and DHA therefore compete for CYP epoxygenase activity (98). Zhang, G et al. looked at the effects of EDPs produced from DHA, on tumor growth. They performed an experiment on C57BL/6 mice to investigate the effects of EDPs and EETs on metastasis using the LLC cell line. When EDPs and EETs were co-administered with an epoxide hydrolase inhibitor, trans-4-[4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid (t-AUCB), EDP inhibited tumor metastasis whereas EET increased tumor metastasis. The role of the epoxide hydrolase inhibitor elevated levels of ω-3 and ω-6 metabolites exaggerating their effects. The results of this experiment suggest that increased levels of ω-3 PUFA metabolites have a positive effect on mice by decreasing lung cancer metastasis. Conversely, the opposite effect is seen with an ω-6 diet.