Thymoquinone Increased Warfarin 7-hydroxylation in Human Liver Microsomes and Induced the Expression of CYP2C9 in HepG2 Cells
Keywords:
Thymoquinone, HPLC-MS/MS method validation, 7-hydroxywarfarin, HepG2 cells, CYP2C9
Abstract
The herbal-drug interaction is an interesting phenomenon that can induce therapeutic complications in patients. Warfarin is widely used as an anticoagulant, which has a narrow therapeutic index. The combination of herbal and warfarin has consequences in the outcome therapy on the attenuation of drug efficacy or increased toxicity. This study aims to investigate the effect of thymoquinone on warfarin 7-hydroxylation activity in human liver microsome (HLM) and the expression of CYP2C9 in HepG2 cells. To investigate the co-administration of thymoquinone on warfarin 7-hydroxylation was conducted using HLM and HepG2 cells. The study was divided into three groups: control, warfarin, and combination of warfarin-thymoquinone. The metabolite of 7-hydroxywarfarin (7-OH warfarin) in HLM was determined using HPLC-MS/MS. Furthermore, the induction effect of thymoquinone on the expression of CYP2C9 in HepG2 cells was determined by RT-PCR. The results of the validated method used were selective for HLM 7-hydroxywarfarin, with an LLOQ of 0.62 μM, and it meets the criteria for accuracy and precision for metabolite analysis. The results showed that the co-incubation of thymoquinone at 0.37mM significantly increased warfarin 7-hydroxylation activity (P < 0.05). In addition, the incubation for 72 hours of thymoquinone also significantly induced the expression of CYP2C9 in HepG2 cells (P < 0.05). These findings provide valuable insights that the combination of thymoquinone with warfarin significantly increased the warfarin 7-hydroxylation activity in human liver microsomes and expression of the CYP2C9 in HepG2 cells, which may have an impact on the clinical outcomes of warfarin in patients.
References
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Holbrook, A.M. (2005). Systematic Overview of Warfarin and Its Drug and Food Interactions. Archives of Internal Medicine, 165(10), 1095. https://doi.org/10.1001/archinte.165.10.1095
Imre, S., Tero-Vescan, A., Dogaru, M.T., Kelemen, L., Muntean, D.L., Curtica˘pean, A., Szegedi, N., & Vari, C.E. (2019). With or Without Internal Standard in HPLC Bioanalysis. A Case Study. Journal of Chromatographic Science, 57(3), 243–248. https://doi.org/10.1093/chromsci/bmy106
Izzo, A.A. (2012). Interactions between Herbs and Conventional Drugs: Overview of the Clinical Data. Medical Principles and Practice, 21(5), 404–428. https://doi.org/10.1159/000334488
Jones, D.R., Kim, S.Y., Guderyon, M., Yun, C.H., Moran, J.H., & Miller, G.P. (2010). Hydroxywarfarin Metabolites Potently Inhibit CYP2C9 Metabolism of S-Warfarin. Chemical Research in Toxicology, 23(5), 939–945. https://doi.org/10.1021/tx1000283
Korashy, H., Al-Jenoobi, F., Raish, M., Ahad, A., Al-Mohizea, A., Alam, M., Alkharfy, K., & Al-Suwayeh, S. (2014). Impact of Herbal Medicines like Nigella sativa, Trigonella foenum-graecum, and Ferula asafoetida, on Cytochrome P450 2C11 Gene Expression in Rat Liver. Drug Research, 65(07), 366–372. https://doi.org/10.1055/s-0034-1384604
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W Ju, K Peng, S Yang, H Sun, M Sampson, & MZ Wang. (2014). A Chiral HPLC-MS/MS Method for Simultaneous Quantification of Warfarin Enantiomers and its Major Hydroxylation Metabolites of CYP2C9 and CYP3A4 in Human Plasma. Austin Journal of Analytical and Pharmaceutical Chemistry, 1(2), 1010.
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Wright, J.M., Wheller, R., Wallace, G., & Green, R. (2019). Internal standards in regulated bioanalysis_putting in place a decision-making process during method development. Bioanalysis, 11(18), 1701–1713. https://doi.org/10.4155/bio-2019-0169
Zhang, Z.Y., Kerr, J., Wexler, R.S., Li, H.,Robinson, A. J., Harlow, P.P., & Kaminsky, L.S. (1997). Warfarin Analog Inhibition of Human CYP2C9-Catalyzed S-Warfarin 7-Hydroxylation. Thrombosis Research, 88, 389–398. https://doi.org/10.1016/s0049-3848(97)00270-3
Albassam, A.A., Ahad, A., Alsultan, A., & Al-Jenoobi, F.I. (2018). Inhibition of cytochrome P450 enzymes by thymoquinone in human liver microsomes. Saudi Pharmaceutical Journal, 26(5), 673–677. https://doi.org/10.1016/j.jsps.2018.02.024
Al-Jenoobi, F.I. (2010). Effects of some commonly used Saudi folk herbal medications on the metabolic activity of CYP2C9 in human liver microsomes. Saudi Pharmaceutical Journal, 18(3), 167–171. https://doi.org/10.1016/j.jsps.2010.05.008
Boerma, J.S., Vermeulen, N.P.E., & Commandeur, J.N.M. (2014). One-electron oxidation of diclofenac by human cytochrome P450s as a potential bioactivation mechanism for formation of 2′-(glutathion-S-yl)-deschloro-diclofenac. Chemico-Biological Interactions, 207, 32–40. https://doi.org/10.1016/j.cbi.2013.11.001
Brantley, S.J., Argikar, A.A., Lin, Y.S., Nagar, S., & Paine, M.F. (2014). Herb–Drug Interactions: Challenges and Opportunities for Improved Predictions. Drug Metabolism and Disposition, 42(3), 301–317. https://doi.org/10.1124/dmd.113.055236
Bruin, M.A.C., de Vries, N., Lucas, L., Rosing, H., Huitema, A.D.R., & Beijnen, J.H. (2020). Development and validation of an integrated LC-MS/MS assay for therapeutic drug monitoring of five PARP-inhibitors. Journal of Chromatography B, 1138, 121925. https://doi.org/10.1016/j.jchromb.2019.121925
Caterina, P., Antonello, D.P., Chiara, G., Chiara, C., Giacomo, L., Antonio, S., Giovambattista, D.S., & Luca, G. (2013). Pharmacokinetic drug‑drug interaction and their implication in clinical management. Journal of Research in Medical Sciences, 18, 601–610.
Chen, Y., & Goldstein, J. (2009). The Transcriptional Regulation of the Human CYP2C Genes. Current Drug Metabolism, 10(6), 567–578. https://doi.org/10.2174/138920009789375397
Committee for Medicinal Products for Human Use. (2011). Guideline-bioanalytical-method-validation. European Medicines Agency.
Corrie, K., & Hardman, J.G. (2014). Mechanisms of drug interactions: Pharmacodynamics and pharmacokinetics. Anaesthesia & Intensive Care Medicine, 15(7), 305–308. https://doi.org/10.1016/j.mpaic.2014.04.005
Daly, A., Rettie, A., Fowler, D., & Miners, J. (2017). Pharmacogenomics of CYP2C9: Functional and Clinical Considerations. Journal of Personalized Medicine, 8(1), 1. https://doi.org/10.3390/jpm8010001
Desjardins, P., & Conklin, D. (2010). Nano Drop Microvolume Quantitation of Nucleic Acids. Journal of Visualized Experiments, 45. https://doi.org/10.3791/2565
Elbarbry, F., Ung, A., & Abdelkawy, K. (2017). Studying the Inhibitory Effect of Quercetin and Thymoquinone on Human Cytochrome P450 Enzyme Activities. Pharmacognosy Magazine, 13(52). http://dx.doi.org/10.4103/0973-1296.224342
Gandhi, V., O’Brien, M.H., & Yadav, S. (2020). High-Quality and High-Yield RNA Extraction Method from Whole Human Saliva. Biomarker Insights, 15, 1–9. https://doi.org/10.1177/1177271920929705
Ge, B., Zhang, Z., & Zuo, Z. (2014). Updates on the Clinical Evidenced Herb-Warfarin Interactions. Evidence-Based Complementary and Alternative Medicine, 2014, 1–18. https://doi.org/10.1155/2014/957362
Goodman, L.S., Gilman, A., Brunton, L.L., & Lazo, J.S. (2010). Goodman Gilmans The Pharmacological Basis of Therapeutics (12th ed.). The McGraw-Hill.
Greenblatt, D.J., & Moltke, L.L. von. (2005). Interaction of Warfarin with Drugs, Natural Substances, and Foods. Journal of Clinical Pharmacology, 45(2), 127–132. https://doi.org/10.1177/0091270004271404
Gupta, R.C., Chang, D., Nammi, S., Bensoussan, A., Bilinski, K., & Roufogalis, B.D. (2017). Interactions between antidiabetic drugs and herbs: An overview of mechanisms of action and clinical implications. Diabetology & Metabolic Syndrome, 9(1), 59. https://doi.org/10.1186/s13098-017-0254-9
Hannan, M.A., Rahman, M.A., Sohag, A.A.M., Uddin, M.J., Dash, R., Sikder, M.H., Rahman, M.S., Timalsina, B., Munni, Y.A., Sarker, P.P., Alam, M., Mohibbullah, M., Haque, M.N., Jahan, I., Hossain, M.T., Afrin, T., Rahman, M.M., Tahjib-Ul-Arif, M., Mitra, S., Oktaviani, D.F., … Kim, B. (2021). Black Cumin (Nigella sativa L.): A Comprehensive Review on Phytochemistry, Health Benefits, Molecular Pharmacology, and Safety. Nutrients, 13(6), 1784. https://doi.org/10.3390/nu13061784
Hassan, S.A., Ahmed, W.A., Galeb, F.M., El-Taweel, M.A., & Abu-Bedair, F.A. (2008). In Vitro Challenge Using Thymoquinone on Hepatocellular Carcinoma (HepG2) Cell Line. Iranian Journal of Pharmaceutical Research, 7 (4), 283–2908. https://doi.org/10.3390/nu13061784.
Holbrook, A.M. (2005). Systematic Overview of Warfarin and Its Drug and Food Interactions. Archives of Internal Medicine, 165(10), 1095. https://doi.org/10.1001/archinte.165.10.1095
Imre, S., Tero-Vescan, A., Dogaru, M.T., Kelemen, L., Muntean, D.L., Curtica˘pean, A., Szegedi, N., & Vari, C.E. (2019). With or Without Internal Standard in HPLC Bioanalysis. A Case Study. Journal of Chromatographic Science, 57(3), 243–248. https://doi.org/10.1093/chromsci/bmy106
Izzo, A.A. (2012). Interactions between Herbs and Conventional Drugs: Overview of the Clinical Data. Medical Principles and Practice, 21(5), 404–428. https://doi.org/10.1159/000334488
Jones, D.R., Kim, S.Y., Guderyon, M., Yun, C.H., Moran, J.H., & Miller, G.P. (2010). Hydroxywarfarin Metabolites Potently Inhibit CYP2C9 Metabolism of S-Warfarin. Chemical Research in Toxicology, 23(5), 939–945. https://doi.org/10.1021/tx1000283
Korashy, H., Al-Jenoobi, F., Raish, M., Ahad, A., Al-Mohizea, A., Alam, M., Alkharfy, K., & Al-Suwayeh, S. (2014). Impact of Herbal Medicines like Nigella sativa, Trigonella foenum-graecum, and Ferula asafoetida, on Cytochrome P450 2C11 Gene Expression in Rat Liver. Drug Research, 65(07), 366–372. https://doi.org/10.1055/s-0034-1384604
Massadeh, A.M., Al-Safi, S.A., Momani, I.F., Al-Mahmoud, M., & Alkofahi, A.S. (2007). Analysis of cadmium and lead in mice organs: Effect of nigella sativa L. (black cumin) on the distribution and immunosuppressive effect of cadmium-lead mixture in mice. Biological Trace Element Research, 115(2), 157–167. https://doi.org/10.1007/BF02686027
Muralidharan-Chari, V., Kim, J., Abuawad, A., Naeem, M., Cui, H., & Mousa, S. (2016). Thymoquinone Modulates Blood Coagulation in Vitro via Its Effects on Inflammatory and Coagulation Pathways. International Journal of Molecular Sciences, 17(4), 474. https://doi.org/10.3390/ijms17040474
Nickavar, B., Mojab, F., Javidnia, K., & Amoli, M. A. R. (2003). Chemical Composition of the Fixed and Volatile Oils of Nigella sativa L. from Iran. Zeitschrift Für Naturforschung C, 58(9–10), 629–631. https://doi.org/10.1515/znc-2003-9-1004
Niu, J., Straubinger, R.M., & Mager, D.E. (2019). Pharmacodynamic Drug–Drug Interactions. Clinical Pharmacology & Therapeutics, 105(6), 1395–1406. https://doi.org/10.1002/cpt.1434
Paarakh, P.M. (2010). Nigella sativa Linn.– A comprehensive review. Indian Journal of Natural Products and Resources, 1(4), 409–429.
Radko, L., Śniegocki, T., Sell, B., & Posyniak, A. (2019). Metabolomic Profile of Primary Turkey and Rat Hepatocytes and Two Cell Lines after Chloramphenicol Exposure. Animals, 10(1), 30. https://doi.org/10.3390/ani10010030
Rombolà, L., Scuteri, D., Marilisa, S., Watanabe, C., Morrone, L.A., Bagetta, G., & Corasaniti, M.T. (2020). Pharmacokinetic Interactions between Herbal Medicines and Drugs: Their Mechanisms and Clinical Relevance. Life, 10(7), 106. https://doi.org/10.3390/life10070106
Śniegocki, T., Gbylik-Sikorska, M., & Posyniak, A. (2017). Analytical strategy for determination of chloramphenicol in different biological matrices by liquid chromatography—Mass spectrometry. Journal of Veterinary Research, 61(3), 321–327. https://doi.org/10.1515/jvetres-2017-0032
Van Booven, D., Marsh, S., McLeod, H., Carrillo, M. W., Sangkuhl, K., Klein, T. E., & Altman, R. B. (2010). Cytochrome P450 2C9-CYP2C9. Pharmacogenetics and Genomics, 20(4), 277–281. https://doi.org/10.1097/FPC.0b013e3283349e84
Vogel, H. G., Maas, J., Hock, F. J., & Mayer, D. (Eds.). (2013). Drug Discovery and Evaluation: Safety and Pharmacokinetic Assays (2nd ed.). Springer Berlin Heidelberg. https://doi.org/10.1007/978-3-642-25240-2
W Ju, K Peng, S Yang, H Sun, M Sampson, & MZ Wang. (2014). A Chiral HPLC-MS/MS Method for Simultaneous Quantification of Warfarin Enantiomers and its Major Hydroxylation Metabolites of CYP2C9 and CYP3A4 in Human Plasma. Austin Journal of Analytical and Pharmaceutical Chemistry, 1(2), 1010.
Wang, Z., Wang, Z., Wang, X., Lv, X., Yin, H., Jiang, L., Xia, Y., Li, W., Li, W., & Liu, Y. (2022). Potential food-drug interaction risk of thymoquinone with warfarin. Chemico-Biological Interactions, 365, 110070. https://doi.org/10.1016/j.cbi.2022.110070
Wright, J.M., Wheller, R., Wallace, G., & Green, R. (2019). Internal standards in regulated bioanalysis_putting in place a decision-making process during method development. Bioanalysis, 11(18), 1701–1713. https://doi.org/10.4155/bio-2019-0169
Zhang, Z.Y., Kerr, J., Wexler, R.S., Li, H.,Robinson, A. J., Harlow, P.P., & Kaminsky, L.S. (1997). Warfarin Analog Inhibition of Human CYP2C9-Catalyzed S-Warfarin 7-Hydroxylation. Thrombosis Research, 88, 389–398. https://doi.org/10.1016/s0049-3848(97)00270-3
Published
2024-06-04
How to Cite
Megawati, A., Nugroho, A. E., Lukitaningsih, E., Prihati, D. A., & Nurrochmad, A. (2024). Thymoquinone Increased Warfarin 7-hydroxylation in Human Liver Microsomes and Induced the Expression of CYP2C9 in HepG2 Cells. Indonesian Journal of Pharmacy. https://doi.org/10.22146/ijp.10966
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