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Ibuprofen Alters Epoxide Hydrolase Activity and Epoxy-Oxylipin Metabolites Associated with Different Metabolic Pathways in Murine Livers

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Ibuprofen Alters Epoxide Hydrolase Activity and Epoxy-Oxylipin Metabolites Associated with Different Metabolic Pathways in Murine Livers UC Davis UC Davis Previously Published Works Title Ibuprofen alters epoxide hydrolase activity and epoxy-oxylipin metabolites associated with different metabolic pathways in murine livers. Permalink https://escholarship.org/uc/item/0zk3c5q2 Journal Scientific reports, 11(1) ISSN 2045-2322 Authors Tiwari, Shuchita Yang, Jun Morisseau, Christophe et al. Publication Date 2021-03-29 DOI 10.1038/s41598-021-86284-1 Peer reviewed eScholarship.org Powered by the California Digital Library University of California www.nature.com/scientificreports OPEN Ibuprofen alters epoxide hydrolase activity and epoxy‑oxylipin metabolites associated with diferent metabolic pathways in murine livers Shuchita Tiwari1, Jun Yang2, Christophe Morisseau2, Blythe Durbin‑Johnson3, Bruce D. Hammock2 & Aldrin V. Gomes 1,4* Over the last decade oxylipins have become more recognized for their involvement in several diseases. Non‑steroidal anti‑infammatory drugs (NSAIDs) such as ibuprofen are known to inhibit cyclooxygenase (COX) enzymes, but how NSAIDs afect oxylipins, in addition to COX products, in animal tissues is not well understood. Oxylipins in livers from male and female mice treated with 100 mg/kg/day of ibuprofen for 7 days were investigated. The results showed that ibuprofen treated male livers contained 7 times more altered oxylipins than ibuprofen treated female livers. In male and female livers some prostaglandins were altered, while diols, hydroxy fatty acids and epoxides were signifcantly altered in male livers. Some soluble epoxide hydrolase (sEH) products, such as 9,10‑DiHODE were found to be decreased, while sEH substrates (such as 9(10)‑EpODE and 5(6)‑EpETrE) were found to be increased in male livers treated with ibuprofen, but not in ibuprofen treated female livers. The enzymatic activities of sEH and microsomal epoxide hydrolase (mEH) were elevated by ibuprofen in both males and females. Analyzing the infuence of sex on the efect of ibuprofen on oxylipins and COX products showed that approximately 27% of oxylipins detected were infuenced by sex. The results reveal that ibuprofen disturbs not only the COX pathway, but also the CYP450 and lipoxygenase pathways in male mice, suggesting that ibuprofen is likely to generate sex related diferences in biologically active oxylipins. Increased sEH activity after ibuprofen treatment is likely to be one of the mechanisms by which the liver reduces the higher levels of EpODEs and EpETrEs. Abbreviations AA Arachidonic acid ALA α-Linolenic acid COX Cyclooxygenase CYP Cytochrome P450 DHA Docosahexaenoic acid EPA Eicosapentaenoic acid CYPe Cytochrome P450 epoxygenase CYPh Cytochrome P450 hydroxylase DiHDPE Dihydroxy-docosapentaenoic acid DiHETrE Dihydroxy-eicosatrienoic acid DiHOME Dihydroxy-octadecenoic acid EPA Eicosapentaenoic acid 1Department of Neurobiology, Physiology, and Behavior, University of California, Davis, CA 95616, USA. 2Department of Entomology and Nematology, and Comprehensive Cancer Center, University of California, Davis, CA 95616, USA. 3Department of Public Health Sciences, University of California, Davis, CA, USA. 4Department of Physiology and Membrane Biology, University of California, Davis, CA, USA. *email: [email protected] Scientifc Reports | (2021) 11:7042 | https://doi.org/10.1038/s41598-021-86284-1 1 Vol.:(0123456789) www.nature.com/scientificreports/ EpETrE Epoxy-eicosatrienoic acid EpOME Epoxy-octadecenoic acid GLA Gamma-linolenic acid HDoHE Hydroxy-docosahexaenoic acid HEPE Hydroxy-eicosapentaenoic acid HETE Hydroxy-eicosatetraenoic acid HETrE Hydroxy-eicosatrienoic acid HHTrE Hydroxy-heptadecatrienoic acid HODE Hydroxy-octadecadienoic acid HOTrE Hydroxy-octadecatrienoic acid LA Linoleic acid LOX Lipoxygenase mEH Microsomal epoxide hydrolase sEH Soluble epoxide hydrolase Ibuprofen is the most common over-the-counter nonsteroidal anti-infammatory drug (NSAID) known for its potent analgesic, anti-infammatory, and antipyretic efects 1. Te therapeutic actions of ibuprofen are mediated by its ability to inhibit the synthesis and release of prostaglandins (PGs) E2 (PGE2) and I2 (PGI2) by blocking cyclooxygenase (COX) enzymes COX-1 and COX-2 which are involved in the generation of pain, fever, and infammation2,3. COX-1 and COX-2 are the rate-determining enzymes for the synthesis of prostaglandins and other prostanoids including thromboxanes and prostacyclins4. Tese molecules play important roles in the immune, cardiovascular, gastrointestinal and renal system3. While COX-1 is important for the protection of gastric mucosa and platelet homeostasis through the formation of protective PGE2 and prostacyclin PGI2, COX-2 is involved with prostaglandin mediated pain and infammation4. Although NSAIDs are some of the most commonly used medicines worldwide, they are associated with various adverse side efects which are generally dose dependent5. Te use of NSAIDs has been associated with gastrointestinal injury, hepatotoxicity, renal and cardiovascular disorders and hypertension6,7. Te NSAIDs benoxaprofen and bromfenac were withdrawn from the market due to severe hepatic toxicity8,9. Similarly, higher incidence of myocardial infarction and stroke led to the withdrawal of rofecoxib and valdecoxib (Bextra)10. In addition, the NSAIDs nimesulide, diclofenac and sudoxicam were reported to cause acute liver injury11,12. In April 2019, Te French National Agency for the Safety of Medicines and Health Products (ANSM) issued a warning regarding the use of NSAIDs (ibuprofen and ketoprofen) for the treatment of patients with infectious diseases13,14. Another concern about ibuprofen is its presence in the environment. Data suggests that fsh health could be adversely afected by the levels of ibuprofen found in rivers15,16. Ibuprofen is also found in drinking water and surface wells. Concerns exist about its possible biological efects when taken regularly in small amounts17,18. Limited studies have investigated the efect of NSAIDs on oxylipins in the P450 branch of the arachidonic acid cascade and these studies largely utilized blood samples. In general, oxylipins regulate a variety of physiological functions by acting as important signaling molecules for specifc receptors or by modulating transcription fac- tors and ion channels in an autocrine manner19. Perturbations in the P450 generated oxylipin concentrations have been shown to be associated with various pathological conditions including chronic pain20,21, diabetes22, Alzheimer’s disease23,24, and cardiovascular diseases25. Oxylipins are bioactive oxidized fatty acid metabolites synthesized by the oxidation of polyunsaturated fatty acids (PUFAs). In a placebo-controlled phase III selenium/celecoxib trial to prevent colorectal adenomatous polyps, blood oxylipins from celecoxib treated participants showed higher levels of individual CYP450 and LOX metabolites and lower levels of COX-derived metabolites compared to placebo treated participants26. However, since circulat- ing oxylipin profles are unlikely to represent tissue profles, and as we have previously shown that ibuprofen was associated with proteasome and metabolic dysfunction in livers 27, the oxylipin profles of livers from ibuprofen treated mice were investigated. We hypothesized that ibuprofen would signifcantly reduce the prostaglandins and thromboxanes that are produced by COX1 and COX2 and would have few efects on non-COX related arachidonic acid pathways. Our data suggest that a moderate dose of ibuprofen treatment for 7 days signifcantly altered oxylipins related to dif- ferent metabolic pathways and revealed signifcant sex specifc diferences in livers from ibuprofen treated males and females relative to their vehicle controls. Materials and methods Animal studies. C57BL/6 J male and female mice (8-week age) were used for the study. Te animal experi- ment was performed in accordance with the protocols approved by the Institutional Animal Care and Use Com- mittee (IACUC) of the University of California, Davis. Tis study is reported in accordance with the ARRIVE guidelines (https:// arriv eguid elines. org). Mice were maintained at controlled temperature and humidity and had free access to food and water. Mice were treated with 100 mg/kg/day of ibuprofen for 7 days in drinking water. Te dose of ibuprofen given to mice would be approximately equivalent to a human taking 486 mg/day as previ- ously described27. Tis dose of ibuprofen is signifcantly lower than the maximum suggested over-the-counter dose (800–1200 mg/day). Te mice were sacrifced, and livers were collected and quickly washed twice in ice- cold phosphate bufered saline (PBS). Te tissues were then pulverized in liquid nitrogen, collected in clean microcentrifuge tubes, and stored at − 80 °C until needed. LC–MS/MS‑based lipidomic analysis. Extraction and analyses of the regulatory lipid mediator: Te extraction process is similar to the protocol as described in a previously published paper28. 10 µL of methanol Scientifc Reports | (2021) 11:7042 | https://doi.org/10.1038/s41598-021-86284-1 2 Vol:.(1234567890) www.nature.com/scientificreports/ containing deuterated internal standard solution, a mixture of d4 PGF1α, d4 TXB2, d4 PGE2, d4 LTB4, d11 14,15 DiHETrE, d6 20 HETE, d4 9 HODE, d8 5 HETE, d11 11,12 EpETrE (Cayman Chemical, Ann Arbor, MI), was added to approximately 100 mg of liver tissue. 400 µL of cold methanol containing 0.1% acetic acid and 0.1% butylated hydroxytoluene, BHT (Sigma-Aldrich, St. Louis, MO) solution was added to these tissue samples and stored at − 80 °C for 30 min. Afer freezing, samples were homogenized
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