Relative Expression of Mouse Udp-glucuronosyl Transferase 2b1 Gene in the Livers, Kidneys, and Hearts: The Influence of Nonsteroidal Anti-inflammatory Drug Treatment

Author(s): Yazun Jarrar*, Qais Jarrar, Mohammad Abu-Shalhoob, Abdulqader abed, Esra'a Sha'ban.

Journal Name: Current Drug Metabolism

Volume 20 , Issue 11 , 2019


Graphical Abstract:


Abstract:

Background: Mouse Udp-glucuronosyl Transferase (UGT) 2b1 is equivalent to the human UGT2B7 enzyme, which is a phase II drug-metabolising enzyme and plays a major role in the metabolism of xenobiotic and endogenous compounds. This study aimed to find the relative expression of the mouse ugt2b1 gene in the liver, kidney, and heart organs and the influence of Nonsteroidal Anti-inflammatory Drug (NSAID) administration.

Methods: Thirty-five Blab/c mice were divided into 5 groups and treated with different commonly-used NSAIDs; diclofenac, ibuprofen, meloxicam, and mefenamic acid for 14 days. The livers, kidneys, and hearts were isolated, while the expression of ugt2b1 gene was analysed with a quantitative real-time polymerase chain reaction technique.

Results: It was found that the ugt2b1 gene is highly expressed in the liver, and then in the heart and the kidneys. NSAIDs significantly upregulated (ANOVA, p < 0.05) the expression of ugt2b1 in the heart, while they downregulated its expression (ANOVA, p < 0.05) in the liver and kidneys. The level of NSAIDs’ effect on ugt2b1 gene expression was strongly correlated (Spearman’s Rho correlation, p < 0.05) with NSAID’s lipophilicity in the liver and its elimination half-life in the heart.

Conclusion: This study concluded that the mouse ugt2b1 gene was mainly expressed in the liver, as 14-day administration of different NSAIDs caused alterations in the expression of this gene, which may influence the metabolism of xenobiotic and endogenous compounds.

Keywords: Drug metabolism, ugt2b1, NSAIDs, gene expression, mouse, liver, kidneys, heart.

[1]
Jancova, P.; Anzenbacher, P.; Anzenbacherova, E. Phase II drug metabolizing enzymes. Biomed. Pap. Med. Fac. Univ. Palacky Olomouc Czech Repub., 2010, 154(2), 103-116.
[http://dx.doi.org/10.5507/bp.2010.017] [PMID: 20668491]
[2]
Knights, K.M.; Winner, L.K.; Elliot, D.J.; Bowalgaha, K.; Miners, J.O. Aldosterone glucuronidation by human liver and kidney microsomes and recombinant UDP-glucuronosyltransferases: Inhibition by NSAIDs. Br. J. Clin. Pharmacol., 2009, 68(3), 402-412.
[http://dx.doi.org/10.1111/j.1365-2125.2009.03469.x] [PMID: 19740398]
[3]
Jarrar, Y.B.; Cha, E.Y.; Seo, K.A.; Ghim, J.L.; Kim, H.J.; Kim, D.H.; Lee, S.J.; Shin, J.G. Determination of major UDP-glucuronosyltransferase enzymes and their genotypes responsible for 20-HETE glucuronidation. J. Lipid Res., 2014, 55(11), 2334-2342.
[http://dx.doi.org/10.1194/jlr.M051169] [PMID: 25249502]
[4]
Du, Z.; Jiao, Y.; Shi, L. Association of UGT2B7 and UGT1A4 polymorphisms with serum concentration of antiepileptic drugs in children. Med. Sci. Monit., 2016, 22, 4107-4113.
[http://dx.doi.org/10.12659/MSM.897626] [PMID: 27795544]
[5]
Ouzzine, M.; Gulberti, S.; Ramalanjaona, N.; Magdalou, J.; Fournel-Gigleux, S. The UDP-glucuronosyltransferases of the blood-brain barrier: Their role in drug metabolism and detoxication. Front. Cell. Neurosci., 2014, 8, 349.
[http://dx.doi.org/10.3389/fncel.2014.00349] [PMID: 25389387]
[6]
Radominska-Pandya, A.; Little, J.M.; Pandya, J.T.; Tephly, T.R.; King, C.D.; Barone, G.W.; Raufman, J.P. UDP-glucuronosyltransferases in human intestinal mucosa. Biochim. Biophys. Acta, 1998, 1394(2-3), 199-208.
[http://dx.doi.org/10.1016/S0005-2760(98)00115-5] [PMID: 9795217]
[7]
Dostalek, M.; Court, M.H.; Hazarika, S.; Akhlaghi, F. Diabetes mellitus reduces activity of human UDP-glucuronosyltransferase 2B7 in liver and kidney leading to decreased formation of mycophenolic acid acyl-glucuronide metabolite. Drug Metab. Dispos., 2011, 39(3), 448-455.
[http://dx.doi.org/10.1124/dmd.110.036608] [PMID: 21123165]
[8]
Hu, D.G.; Mackenzie, P.I.; Lu, L.; Meech, R.; McKinnon, R.A. Induction of human UDP-Glucuronosyltransferase 2B7 gene expression by cytotoxic anticancer drugs in liver cancer HepG2 cells. Drug Metab. Dispos., 2015, 43(5), 660-668.
[http://dx.doi.org/10.1124/dmd.114.062380] [PMID: 25713207]
[9]
Issa, N.T.; Wathieu, H.; Ojo, A.; Byers, S.W.; Dakshanamurthy, S. Drug metabolism in preclinical drug development: A survey of the discovery process, toxicology, and computational tools. Curr. Drug Metab., 2017, 18(6), 556-565.
[http://dx.doi.org/10.2174/1389200218666170316093301] [PMID: 28302026]
[10]
Fujiwara, R.; Yoda, E.; Tukey, R.H. Species differences in drug glucuronidation: Humanized UDP-glucuronosyltransferase 1 mice and their application for predicting drug glucuronidation and drug-induced toxicity in humans. Drug Metab. Pharmacokinet., 2018, 33(1), 9-16.
[http://dx.doi.org/10.1016/j.dmpk.2017.10.002] [PMID: 29079228]
[11]
Buckley, D.B.; Klaassen, C.D. Tissue- and gender-specific mRNA expression of UDP-glucuronosyltransferases (UGTs) in mice. Drug Metab. Dispos., 2007, 35(1), 121-127.
[http://dx.doi.org/10.1124/dmd.106.012070] [PMID: 17050650]
[12]
Jarrar, Y.B.; Jarrar, Q.; Abed, A.; Abu-Shalhoob, M. Effects of nonsteroidal anti-inflammatory drugs on the expression of arachidonic acid-metabolizing Cyp450 genes in mouse hearts, kidneys and livers. Prostaglandins Other Lipid Mediat., 2019, 141, 14-21.
[http://dx.doi.org/10.1016/j.prostaglandins.2019.02.003] [PMID: 30763676]
[13]
Simmons, D.L.; Wagner, D.; Westover, K. Nonsteroidal anti-inflammatory drugs, acetaminophen, cyclooxygenase 2, and fever. Clin. Infect. Dis., 2000, 31(Suppl. 5), S211-S218.
[http://dx.doi.org/10.1086/317517] [PMID: 11113025]
[14]
Xie, G.; Wong, C.C.; Cheng, K.W.; Huang, L.; Constantinides, P.P.; Rigas, B. Regioselective oxidation of phospho-NSAIDs by human cytochrome P450 and flavin monooxygenase isoforms: Implications for their pharmacokinetic properties and safety. Br. J. Pharmacol., 2012, 167(1), 222-232.
[http://dx.doi.org/10.1111/j.1476-5381.2012.01982.x] [PMID: 22489789]
[15]
Kuehl, G.E.; Lampe, J.W.; Potter, J.D.; Bigler, J. Glucuronidation of nonsteroidal anti-inflammatory drugs: Identifying the enzymes responsible in human liver microsomes. Drug Metab. Dispos., 2005, 33(7), 1027-1035.
[http://dx.doi.org/10.1124/dmd.104.002527] [PMID: 15843492]
[16]
Joo, J.; Kim, Y.W.; Wu, Z.; Shin, J.H.; Lee, B.; Shon, J.C.; Lee, E.Y.; Phuc, N.M.; Liu, K.H. Screening of non-steroidal anti-inflammatory drugs for inhibitory effects on the activities of six UDP-glucuronosyltransferases (UGT1A1, 1A3, 1A4, 1A6, 1A9 and 2B7) using LC-MS/MS. Biopharm. Drug Dispos., 2015, 36(4), 258-264.
[http://dx.doi.org/10.1002/bdd.1933] [PMID: 25522350]
[17]
Rowsell, H.C. The Canadian council on animal care-its guidelines and policy directives: The veterinarian’s responsibility. Can. J. Vet. Res., 1991, 55(3), 205.
[PMID: 1889029]
[18]
Nair, A.B.; Jacob, S. A simple practice guide for dose conversion between animals and human. J. Basic Clin. Pharm., 2016, 7(2), 27-31.
[http://dx.doi.org/10.4103/0976-0105.177703] [PMID: 27057123]
[19]
Jarrar, Y.B.; Al-Essa, L.; Kilani, A.; Hasan, M.; Al-Qerem, W. Alterations in the gene expression of drug and arachidonic acid-metabolizing Cyp450 in the livers of controlled and uncontrolled insulin-dependent diabetic mice. Diabetes Metab. Syndr. Obes., 2018, 11, 483-492.
[http://dx.doi.org/10.2147/DMSO.S172664] [PMID: 30288071]
[20]
Livak, K.J.; Schmittgen, T.D. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods, 2001, 25(4), 402-408.
[http://dx.doi.org/10.1006/meth.2001.1262] [PMID: 11846609]
[21]
Lee, Y-A.; Hong, S-J.; Lee, S-H.; Yang, H-I. Perioperative medication management in arthritic patients. J. Korean Rheum. Assoc., 2008, 15(2), 101-109.
[http://dx.doi.org/10.4078/jkra.2008.15.2.101]
[22]
Park, K.; Bavry, A.A. Risk of stroke associated with nonsteroidal anti-inflammatory drugs. Vasc. Health Risk Manag., 2014, 10, 25-32.
[PMID: 24421643]
[23]
McGettigan, P.; Henry, D. Cardiovascular risk and inhibition of cyclooxygenase: A systematic review of the observational studies of selective and nonselective inhibitors of cyclooxygenase 2. JAMA, 2006, 296(13), 1633-1644.
[http://dx.doi.org/10.1001/jama.296.13.jrv60011] [PMID: 16968831]
[24]
Kim, S.; Chen, J.; Cheng, T.; Gindulyte, A.; He, J.; He, S.; Li, Q.; Shoemaker, B.A.; Thiessen, P.A.; Yu, B.; Zaslavsky, L.; Zhang, J.; Bolton, E.E. PubChem 2019 update: Improved access to chemical data. Nucleic Acids Res., 2019, 47(D1), D1102-D1109.
[http://dx.doi.org/10.1093/nar/gky1033] [PMID: 30371825]
[25]
Meyer, U.A. Overview of enzymes of drug metabolism. J. Pharmacokinet. Biopharm., 1996, 24(5), 449-459.
[http://dx.doi.org/10.1007/BF02353473] [PMID: 9131484]
[26]
Girard, C.; Barbier, O.; Veilleux, G.; El-Alfy, M.; Bélanger, A. Human uridine diphosphate-glucuronosyltransferase UGT2B7 conjugates mineralocorticoid and glucocorticoid metabolites. Endocrinology, 2003, 144(6), 2659-2668.
[http://dx.doi.org/10.1210/en.2002-0052] [PMID: 12746330]
[27]
Lee, S.H.; Han, C.D.; Yang, I.H.; Ha, C.W. Prescription pattern of NSAIDs and the prevalence of NSAID-induced gastrointestinal risk factors of orthopaedic patients in clinical practice in Korea. J. Korean Med. Sci., 2011, 26(4), 561-567.
[http://dx.doi.org/10.3346/jkms.2011.26.4.561] [PMID: 21468265]
[28]
Al-Shidhani, A.; Al-Rawahi, N.; Al-Rawahi, A.; Sathiya Murthi, P. Non-steroidal Anti-inflammatory Drugs (NSAIDs) use in primary health care centers in A’Seeb, Muscat: A clinical audit. Oman Med. J., 2015, 30(5), 366-371.
[http://dx.doi.org/10.5001/omj.2015.73] [PMID: 26421118]
[29]
Sriuttha, P.; Sirichanchuen, B.; Permsuwan, U. Hepatotoxicity of nonsteroidal anti-inflammatory drugs: A systematic review of randomized controlled trials. Int. J. Hepatol., 2018, 20185253623
[http://dx.doi.org/10.1155/2018/5253623] [PMID: 29568654]
[30]
Almansour, M.I.; Jarrar, Y.B.; Jarrar, B.M. In vivo investigation on the chronic hepatotoxicity induced by sertraline. Environ. Toxicol. Pharmacol., 2018, 61, 107-115.
[http://dx.doi.org/10.1016/j.etap.2018.05.021] [PMID: 29883902]
[31]
Verbeeck, R.K.; Wallace, S.M. Non-steroidal anti-inflammatory drugs: Restrictive or non-restrictive hepatic clearance? Arzneimittelforschung, 1994, 44(5), 683-685.
[PMID: 8024649]
[32]
Knights, K.M.; Rowland, A.; Miners, J.O. Renal drug metabolism in humans: The potential for drug-endobiotic interactions involving Cytochrome P450 (CYP) and UDP-glucuronosyltransferase (UGT). Br. J. Clin. Pharmacol., 2013, 76(4), 587-602.
[http://dx.doi.org/10.1111/bcp.12086] [PMID: 23362865]
[33]
Bowalgaha, K.; Miners, J.O. The glucuronidation of mycophenolic acid by human liver, kidney and jejunum microsomes. Br. J. Clin. Pharmacol., 2001, 52(5), 605-609.
[http://dx.doi.org/10.1046/j.0306-5251.2001.01487.x] [PMID: 11736871]
[34]
Abdeen, A.; Aboubakr, M.; Elgazzar, D.; Abdo, M.; Abdelkader, A.; Ibrahim, S.; Elkomy, A. Rosuvastatin attenuates piroxicam-mediated gastric ulceration and hepato-renal toxicity in rats. Biomed. Pharmacother., 2019, 110, 895-905.
[http://dx.doi.org/10.1016/j.biopha.2018.11.004] [PMID: 30572194]
[35]
Jarrar, Q.B.; Hakim, M.N.; Cheema, M.S.; Zakaria, Z.A. Comparative ultrastructural hepatic alterations induced by free and liposome-encapsulated mefenamic acid. Ultrastruct. Pathol., 2017, 41(5), 335-345.
[http://dx.doi.org/10.1080/01913123.2017.1349850] [PMID: 28829237]
[36]
Gui, S.; Sang, X.; Zheng, L.; Ze, Y.; Zhao, X.; Sheng, L.; Sun, Q.; Cheng, Z.; Cheng, J.; Hu, R.; Wang, L.; Hong, F.; Tang, M. Intragastric exposure to titanium dioxide nanoparticles induced nephrotoxicity in mice, assessed by physiological and gene expression modifications. Part. Fibre Toxicol., 2013, 10, 4.
[http://dx.doi.org/10.1186/1743-8977-10-4] [PMID: 23406204]
[37]
Kucey, A.S.; Velenosi, T.J.; Tonial, N.C.; Tieu, A. RaoPeters, A.A.E.; Urquhart, B.L. The effect of chronic kidney disease on CYP2B expression and activity in male Wistar rats. Pharmacol. Res. Perspect., 2019, 7(3)e00475
[http://dx.doi.org/10.1002/prp2.475] [PMID: 31049204]


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Article Details

VOLUME: 20
ISSUE: 11
Year: 2019
Page: [918 - 923]
Pages: 6
DOI: 10.2174/1389200220666191115103310
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