Relative Importance of Soluble and Microsomal Epoxide Hydrolases for the Hydrolysis of Epoxy-Fatty Acids in Human Tissues
Epoxy-fatty acids (EpFAs) are endogenous lipid mediators that have a large breadth of biological activities, including the regulation of blood pressure, inflammation, angiogenesis, and pain perception. For the past 20 years, soluble epoxide hydrolase (sEH) has been recognized as the primary enzyme f...
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| Format: | Article |
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MDPI AG
2021-05-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/22/9/4993 |
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| author | Christophe Morisseau Sean D. Kodani Shizuo G. Kamita Jun Yang Kin Sing Stephen Lee Bruce D. Hammock |
| author_facet | Christophe Morisseau Sean D. Kodani Shizuo G. Kamita Jun Yang Kin Sing Stephen Lee Bruce D. Hammock |
| author_sort | Christophe Morisseau |
| collection | DOAJ |
| description | Epoxy-fatty acids (EpFAs) are endogenous lipid mediators that have a large breadth of biological activities, including the regulation of blood pressure, inflammation, angiogenesis, and pain perception. For the past 20 years, soluble epoxide hydrolase (sEH) has been recognized as the primary enzyme for degrading EpFAs in vivo. The sEH converts EpFAs to the generally less biologically active 1,2-diols, which are quickly eliminated from the body. Thus, inhibitors of sEH are being developed as potential drug therapeutics for various diseases including neuropathic pain. Recent findings suggest that other epoxide hydrolases (EHs) such as microsomal epoxide hydrolase (mEH) and epoxide hydrolase-3 (EH3) can contribute significantly to the in vivo metabolism of EpFAs. In this study, we used two complementary approaches to probe the relative importance of sEH, mEH, and EH3 in 15 human tissue extracts: hydrolysis of 14,15-EET and 13,14-EDP using selective inhibitors and protein quantification. The sEH hydrolyzed the majority of EpFAs in all of the tissues investigated, mEH hydrolyzed a significant portion of EpFAs in several tissues, whereas no significant role in EpFAs metabolism was observed for EH3. Our findings indicate that residual mEH activity could limit the therapeutic efficacy of sEH inhibition in certain organs. |
| first_indexed | 2024-03-10T11:36:25Z |
| format | Article |
| id | doaj.art-476ff33ddda041e8a1e85797f0b60e25 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T11:36:25Z |
| publishDate | 2021-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-476ff33ddda041e8a1e85797f0b60e252023-11-21T18:47:46ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-05-01229499310.3390/ijms22094993Relative Importance of Soluble and Microsomal Epoxide Hydrolases for the Hydrolysis of Epoxy-Fatty Acids in Human TissuesChristophe Morisseau0Sean D. Kodani1Shizuo G. Kamita2Jun Yang3Kin Sing Stephen Lee4Bruce D. Hammock5Department of Entomology and Nematology, U.C. Davis Comprehensive Cancer Center, University of California Davis, Davis, CA 95616, USADepartment of Entomology and Nematology, U.C. Davis Comprehensive Cancer Center, University of California Davis, Davis, CA 95616, USADepartment of Entomology and Nematology, U.C. Davis Comprehensive Cancer Center, University of California Davis, Davis, CA 95616, USADepartment of Entomology and Nematology, U.C. Davis Comprehensive Cancer Center, University of California Davis, Davis, CA 95616, USADepartment of Entomology and Nematology, U.C. Davis Comprehensive Cancer Center, University of California Davis, Davis, CA 95616, USADepartment of Entomology and Nematology, U.C. Davis Comprehensive Cancer Center, University of California Davis, Davis, CA 95616, USAEpoxy-fatty acids (EpFAs) are endogenous lipid mediators that have a large breadth of biological activities, including the regulation of blood pressure, inflammation, angiogenesis, and pain perception. For the past 20 years, soluble epoxide hydrolase (sEH) has been recognized as the primary enzyme for degrading EpFAs in vivo. The sEH converts EpFAs to the generally less biologically active 1,2-diols, which are quickly eliminated from the body. Thus, inhibitors of sEH are being developed as potential drug therapeutics for various diseases including neuropathic pain. Recent findings suggest that other epoxide hydrolases (EHs) such as microsomal epoxide hydrolase (mEH) and epoxide hydrolase-3 (EH3) can contribute significantly to the in vivo metabolism of EpFAs. In this study, we used two complementary approaches to probe the relative importance of sEH, mEH, and EH3 in 15 human tissue extracts: hydrolysis of 14,15-EET and 13,14-EDP using selective inhibitors and protein quantification. The sEH hydrolyzed the majority of EpFAs in all of the tissues investigated, mEH hydrolyzed a significant portion of EpFAs in several tissues, whereas no significant role in EpFAs metabolism was observed for EH3. Our findings indicate that residual mEH activity could limit the therapeutic efficacy of sEH inhibition in certain organs.https://www.mdpi.com/1422-0067/22/9/4993epoxy-fatty acidepoxide hydrolasecardiovascular diseaseinflammationpain |
| spellingShingle | Christophe Morisseau Sean D. Kodani Shizuo G. Kamita Jun Yang Kin Sing Stephen Lee Bruce D. Hammock Relative Importance of Soluble and Microsomal Epoxide Hydrolases for the Hydrolysis of Epoxy-Fatty Acids in Human Tissues International Journal of Molecular Sciences epoxy-fatty acid epoxide hydrolase cardiovascular disease inflammation pain |
| title | Relative Importance of Soluble and Microsomal Epoxide Hydrolases for the Hydrolysis of Epoxy-Fatty Acids in Human Tissues |
| title_full | Relative Importance of Soluble and Microsomal Epoxide Hydrolases for the Hydrolysis of Epoxy-Fatty Acids in Human Tissues |
| title_fullStr | Relative Importance of Soluble and Microsomal Epoxide Hydrolases for the Hydrolysis of Epoxy-Fatty Acids in Human Tissues |
| title_full_unstemmed | Relative Importance of Soluble and Microsomal Epoxide Hydrolases for the Hydrolysis of Epoxy-Fatty Acids in Human Tissues |
| title_short | Relative Importance of Soluble and Microsomal Epoxide Hydrolases for the Hydrolysis of Epoxy-Fatty Acids in Human Tissues |
| title_sort | relative importance of soluble and microsomal epoxide hydrolases for the hydrolysis of epoxy fatty acids in human tissues |
| topic | epoxy-fatty acid epoxide hydrolase cardiovascular disease inflammation pain |
| url | https://www.mdpi.com/1422-0067/22/9/4993 |
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