Investigation of in Vitro and in Vivo Metabolism of Schisandrin B from Schisandrae Fructus by Liquid Chromatography Coupled Electrospray Ionization Tandem Mass Spectrometry

Abstract

Schisandrin B (Sch B) is one of the active dibenzocyclooctadiene lignans found in the Schisandrae Fructus. Experimental studies have shown that Sch B possesses various pharmacological properties, including anti-cancer, neuroprotective and nephroprotective activities. However, no detailed information on its biotransformation was reported in the literature. Here, we investigated the in vitro and in vivo metabolism of Sch B by using ultra-performance liquid chromatography coupled with tandem mass spectrometry. In vitro study detected and identified one oxygenated metabolite. Four metabolites were detected and identified from the in vivo study. The results indicated that the metabolism of Sch B mainly involved the demethylation of methoxy groups, the opening of five-member ring and the glucuronidation of metabolites in rats. The metabolites were identified for the first time by MS/MS analyses.

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Qian, T. , Leong, P. , Ko, K. and Chan, W. (2015) Investigation of in Vitro and in Vivo Metabolism of Schisandrin B from Schisandrae Fructus by Liquid Chromatography Coupled Electrospray Ionization Tandem Mass Spectrometry. Pharmacology & Pharmacy, 6, 363-373. doi: 10.4236/pp.2015.68037.

Conflicts of Interest

The authors declare no conflicts of interest.

References

[1] Hancke, J.L., Burgos, R.A. and Ahumada, F. (1999) Schisandra chinensis. (Turcz.) Baill. Fitoterapia, 70, 451-471.
http://dx.doi.org/10.1016/S0367-326X(99)00102-1
[2] Balandin, D.A. (1951) Schizandrin—A New Stimulant from Schizandra Fruits. In: Lazarev, N.V., Ed., Materials for the Study of Stimulants and Tonics from Ginseng and Schizandra Roots, Far East Branch of USSR Academy of Science, Vladivotok, 45-50.
[3] Liu, X., Zhang, C., Jin, X., Li, Y., Zheng, X. and Li, L. (2007) Inhibitory Effect of Schisandrin B on Gastric Cancer Cells in Vitro. World Journal of Gastroenterology, 13, 6506-6511.
http://dx.doi.org/10.3748/wjg.13.6506
[4] Li, L., Lu, Q., Shen, Y. and Hu, X. (2006) Schisandrin B Enhances Doxorubicin-Induced Apoptosis of Cancer Cells but Not Normal Cells. Biochemical Pharmacology, 71, 584-595.
http://dx.doi.org/10.1016/j.bcp.2005.11.026
[5] Li, L., Wang, T., Xu, Z., Yu, Y., Chen, W. and Chen, F. (2005) Effects of Schisandrin B on Reversing Multidrug Resistance in Human Breast Cancer Cells Transfected with mdr1 Gene. Chinese Medical Journal, 85, 1633-1637.
[6] Xu, Y., Liu, Z., Sun, J., Pan, Q., Sun, F., Yan, Z. and Hu, X. (2011) Schisandrin B Prevents Doxorubicin-Induced Chronic Cardiotoxicity and Enhances Its Anticancer Activity in Vivo. PLoS ONE, 6, e28335.
http://dx.doi.org/10.1371/journal.pone.0028335
[7] Chen, Y., Ip, S.P., Ko, K.M., Poon, T.C., Ng, E.W., Lai, P,B., Mao, Q.Q., Xian, Y.F. and Che, C.T. (2011) A Proteomic Approach in Investigating the Hepatoprotective Mechanism of Schisandrin B: Role of Raf Kinase Inhibitor Protein. Journal of Proteome Research, 10, 299-304.
http://dx.doi.org/10.1021/pr100871h
[8] Leong, P.K., Chiu, P.Y., Leung, H.Y. and Ko, K.M. (2012) Cytochrome P450-Catalysed Reactive Oxygen Species Production Mediates the (?)Schisandrin B-Induced Glutathione and Heat Shock Responses in AML12 Hepatocytes. Cell Biology International, 36, 321-326.
http://dx.doi.org/10.1042/CBI20090451
[9] Pu, H.J., Cao, Y.F., He, R.R., Zhao, Z.L., Song, J.H., Jiang, B., Huang, T., Tang, S.H., Lu, J.M. and Kurihara, H. (2012) Correlation between Antistress and Hepatoprotective Effects of Schisandra Lignans Was Related with Its Antioxidative Actions in Liver Cells. Evidence-Based Complementary and Alternative Medicine, 2012, Article ID: 161062.
http://dx.doi.org/10.1155/2012/161062
[10] Chiu, P.Y., Leung, H.Y., Siu, A.H., Poon, M.K. and Ko, K.M. (2007) Schisandrin B Decreases the Sensitivity of Mitochondria to Calcium Ion-Induced Permeability Transition and Protects against Carbon Tetrachloride Toxicity in Mouse Livers. Biological and Pharmaceutical Bulletin, 30, 1108-1112.
http://dx.doi.org/10.1248/bpb.30.1108
[11] Pan, S.Y., Han, Y.F., Carlier, P.R., Pang, Y.P., Mak, D.H., Lam, B.Y. and Ko, K.M. (2002) Schisandrin B Protects against Tacrine- and Bis(7)-Tacrine-Induced Hepatotoxicity and Enhances Cognitive Function in Mice. Planta Medica, 68, 217-220.
http://dx.doi.org/10.1055/s-2002-23145
[12] Chiu, P.Y., Tang, M.H. and Ko, K.M. (2003) Hepatoprotective Mechanism of Schisandrin B: Role of Mitochondrial Glutathione Antioxidant Status and Heat Shock Proteins. Free Radical Biology and Medicine, 35, 368-380.
http://dx.doi.org/10.1016/S0891-5849(03)00274-0
[13] Stacchiotti, A., Volti, G.L. and Rodella, L.F. (2009) Schisandrin B Stimulates a Cytoprotective Response in Rat Liver Exposed to Mercuric Chloride. Food and Chemical Toxicology, 47, 2834-2840.
http://dx.doi.org/10.1016/j.fct.2009.09.003
[14] Li, L., Zhang, T., Zhou, L., Xing, G., Chen, Y. and Xin, Y. (2013) Schisandrin B Attenuates Acetaminophen-Induced Hepatic Injury through Overexpression of Heat Shock Protein 27 and 70 in Mice. Journal of Gastroenterology and Hepatology, 23, 640-647.
[15] Pan, S.Y., Jia, Z.H., Zhang, Y., Yu, Q., Wang, X.Y., Sun, N., Zhu, P.L., Yu, Z.L. and Ko, K.M. (2013) A Novel Mouse Model of Combined Hyperlipidemia Associated with Steatosis and Liver Injury by a Single-Dose Intragastric Administration of Schisandrin B/Cholesterol/Bile Salts Mixture. Journal of Pharmacological Sciences, 123, 110-119.
http://dx.doi.org/10.1254/jphs.13087FP
[16] Pao, T.T., Hsu, K.F., Liu, K.T., Chang, L.G., Chuang, C.H. and Sung, C.Y. (1977) Protective Action of Schizandrin B on Hepatic Injury in Mice. Chinese Medical Journal (English Edition), 3, 173-179.
[17] Bunel, V., Antoine, M.H., Nortier, J., Duez, P. and Stévigny, C. (2013) Protective Effects of Schizandrin and Schizandrin B towards Cisplatin Nephrotoxicity in Vitro. Journal of Applied Toxicology, 34, 1311-1319.
http://dx.doi.org/10.1002/jat.2951
[18] Li, M., Jin, J., Li, J., Guan, C.W., Wang, W.W., Qiu, Y.W. and Huang, Z.Y. (2012) Schisandrin B Protects against Nephrotoxicity Induced by Cisplatin in HK-2 Cells via Nrf2-ARE Activation. Acta Pharmaceutica Sinica, 47, 1434-1439.
[19] Zhu, S., Wang, Y., Chen, M., Jin, J., Qiu, Y., Huang, M. and Huang, Z. (2012) Protective Effect of Schisandrin B against Cyclosporine A-Induced Nephrotoxicity in Vitro and in Vivo. The American Journal of Chinese Medicine, 40, 551-566.
http://dx.doi.org/10.1142/S0192415X12500425
[20] Chiu, P.Y., Leung, H.Y. and Ko, K.M. (2008) Schisandrin B Enhances Renal Mitochondrial Antioxidant Status, Functional and Structural Integrity, and Protects against Gentamicin-Induced Nephrotoxicity in Rats. Biological and Pharmaceutical Bulletin, 31, 602-605.
http://dx.doi.org/10.1248/bpb.31.602
[21] Stacchiotti, A., Volti, G., Lavazza, A., Schena, I., Aleo, M.F., Rodella, L.F. and Rezzani, R. (2011) Different Role of Schisandrin B on Mercury-Induced Renal Damage in Vivo and in Vitro. Toxicology, 286, 48-57.
http://dx.doi.org/10.1016/j.tox.2011.05.005
[22] Liu, W., Xu, Z., Yang, H., Deng, Y., Xu, B. and Wei, U. (2011) The Protective Effects of Tea Polyphenols and Schisandrin B on Nephrotoxicity of Mercury. Biological Trace Element Research, 143, 1651-1665.
http://dx.doi.org/10.1007/s12011-011-8996-y
[23] Chiu, P.Y., Lam, P.Y., Yan, C.W. and Ko, K.M. (2011) Schisandrin B Protects against Solar Irradiation-Induced Oxidative Injury in BJ Human Fibroblasts. Fitoterapia, 82, 682-691.
http://dx.doi.org/10.1016/j.fitote.2011.02.010
[24] Ip, S.P. and Ko, K.M. (1996) The Crucial Antioxidant Action of Schisandrin B in Protecting against Carbon Tetrachloride Hepatotoxicity in Mice: A Comparative Study with Butylated Hydroxytoluene. Biochemical Pharmacology, 52, 1687-1693.
http://dx.doi.org/10.1016/S0006-2952(96)00517-5
[25] Xue, J., Liu, G., Wei, H. and Pan, Y. (1992) Antioxidant Activity of Two Dibenzocyclooctene Lignans on the Aged and Ischemic Brain in Rats. Free Radical Biology and Medicine, 12, 127-135.
http://dx.doi.org/10.1016/0891-5849(92)90006-3
[26] Zhang, T.M., Wang, B.E. and Liu, G.T. (1989) Action of Schizandrin B, an Antioxidant, on Lipid Peroxidation in Primary Cultured Hepatocytes. Acta Pharmacologica Sinica, 10, 353-356. (Article in Chinese)
[27] Giridharan, V.V., Thandavarayan, R.A., Sato, S., Ko, K.M. and Konishi, T. (2011) Prevention of Scopolamine-Induced Memory Deficits by Schisandrin B, an Antioxidant Lignan from Schisandra chinensis in Mice. Free Radical Research, 45, 950-958.
http://dx.doi.org/10.3109/10715762.2011.571682
[28] Lam, P.Y., Yan, C.W. and Ko, K.M. (2011) Schisandrin B Protects against Solar Irradiation-Induced Oxidative Stress in Rat Skin Tissue. Fitoterapia, 82, 393-400.
http://dx.doi.org/10.1016/j.fitote.2010.11.018
[29] Checker, R., Patwardhan, R.S. and Sandur, S.K. (2012) Schisandrin B Exhibits Anti-Inflammatory Activity through Modulation of the Redox-Sensitive Transcription Factors Nrf2 and NF-kB. Free Radical Biology and Medicine, 53, 1421-1430.
http://dx.doi.org/10.1016/j.freeradbiomed.2012.08.006
[30] Lam, P.Y. and Ko, K.M. (2012) Beneficial Effect of (-)Schisandrin B against 3-Nitropropionic Acid-Induced Cell Death in PC12 Cells. Biofactors, 38, 219-225.
http://dx.doi.org/10.1002/biof.1009
[31] Lee, T.H., Jung, C.H. and Lee, D.H. (2012) Neuroprotective Effects of Schisandrin B against Transient Focal Cerebral Ischemia in Sprague-Dawley Rats. Food and Chemical Toxicology, 50, 4239-4245.
http://dx.doi.org/10.1016/j.fct.2012.08.047
[32] Zeng, K., Zhang, T., Fu, H., Liu, G. and Wang, X. (2012) Schisandrin B Exerts Anti-Neuroinflammatory Activity by Inhibiting the Toll-Like Receptor 4-Dependent MyD88/IKK/NF-κB Signaling Pathway in Lipopolysaccharide-Induced Microglia. European Journal of Pharmacology, 692, 29-37.
http://dx.doi.org/10.1016/j.ejphar.2012.05.030
[33] Wang, B. and Wang, X. (2009) Schisandrin B Protects Rat Cortical Neurons against Abeta1-42-Induced Neurotoxicity. Pharmazie, 64, 450-454.
[34] Lam, P.Y. and Ko, K.M. (2012) Schisandrin B as a Hormetic Agent for Preventing Age-Related Neurodegenerative Diseases. Oxidative Medicine and Cellular Longevity, 2012, Article ID: 250825.
http://dx.doi.org/10.1155/2012/250825
[35] Chen, N., Chiu, P.Y. and Ko, K.M. (2008) Schisandrin B Enhances Cerebral Mitochondrial Antioxidant Status and Structural Integrity, and Protects against Cerebral Ischemia/Reperfusion Injury in Rats. Biological and Pharmaceutical Bulletin, 31, 1387-1391.
http://dx.doi.org/10.1248/bpb.31.1387
[36] Ko, K.M. and Lam, B.Y. (2002) Schisandrin B Protects against Tert-Butylhydroperoxide Induced Cerebral Toxicity by Enhancing Glutathione Antioxidant Status in Mouse Brain. Molecular and Cellular Biochemistry, 238, 181-186.
http://dx.doi.org/10.1023/A:1019907316129
[37] Zhu, H., Zhang, X., Guan, J., Cui, B., Zhao, L. and Zhao, X. (2013) Pharmacokinetics and Tissue Distribution Study of Schisandrin B in Rats by Ultra-Fast Liquid Chromatography with Tandem Mass Spectrometry. Journal of Pharmaceutical and Biomedical Analysis, 78-79, 136-140.
http://dx.doi.org/10.1016/j.jpba.2013.01.041
[38] Sun, H., Wu, F., Zhang, A., Wei, W., Han, Y. and Wang, X. (2013) Profiling and Identification of the Absorbed Constituents and Metabolites of Schisandra Lignans by Ultra-Performance Liquid Chromatography Coupled to Mass Spectrometry. Biomedical Chromatography, 27, 1511-1519.
http://dx.doi.org/10.1002/bmc.2951
[39] Wang, B.L., Hu, J.P. and Li, Y. (2008) Simultaneous Quantification of Four Active Schisandra Lignans from a Traditional Chinese Medicine Schisandra chinensis (Wuweizi) in Rat Plasma Using Liquid Chromatography/Mass Spectrometry. Journal of Chromatography B, 865, 114-120.
http://dx.doi.org/10.1016/j.jchromb.2008.02.016
[40] Huang, X., Song, F., Liu, Z. and Liu, S. (2007) Studies on Lignan Constituents from Schisandra chinensis (Turcz.) Baill. Fruits Using High-Performance Liquid Chromatography/Electrospray Ionization Multiple-Stage Tandem Mass Spectrometry. Journal of Mass Spectrometry, 42, 1148-1161.
http://dx.doi.org/10.1002/jms.1246
[41] Tang, J., Shao, B., Liu, Y., Liu, H., Ji, H., Zhu, D. and Wu, L. (2010) Highly Sensitive Determination of Schisandrin and Schisandrin B in Plasma of Rats after Administration of Wurenchun (Fructus Schisandrae Chinensis Extracts) Preparations by LC-ESI-MS/MS. Biomedical Chromatography, 24, 675-681.
[42] Sun, H., Wu, F., Zhang, A., Wei, W., Han, Y. and Wang, X. (2013) Pharmacokinetic Study of Schisandrin, Schisandrol B, Schisantherin A, Deoxyschisandrin, and Schisandrin B in Rat Plasma after Oral Administration of Shengmaisan Formula by UPLC-MS. Journal of Separation Science, 36, 485-491.
http://dx.doi.org/10.1002/jssc.201200887
[43] He, R., Tan, P., Han, J., Lin, H., Chen, X., Liu, Y. and Zhang, Y. (2013) ESI/MS Study on Fragmentation Pathways of Schisandrin B by the Discovery Studio, World Science and Technology/Modernization of Traditional Chinese Medicine and Materia. Medica, 15, 527-530.
[44] Corveia, M.A. and Montellauo, P.O. (2005) Inhibition of Cytochrome P450 Enzymes. In: Ortiz de Montellano, P.R., Ed., Cytochrome P450: Structure, Mechanism and Biochemistry, Kluwer Academic, New York, 263-365.
[45] Iwata, H., Tezuka, Y., Kadota, S., Hiratsuka, A. and Watabe, T. (2004) Identification and Characterization of Potent CYP3A4 Inhibitors in Schisandra Fruit Extract. Drug Metabolism and Disposition, 32, 1351-1358.
http://dx.doi.org/10.1124/dmd.104.000646
[46] Donato, M.T. and Castell, J.V. (2003) Strategies and Molecular Probes to Investigate the Role of Cytochrome P450 in Drug Metabolism: Focus on in Vitro Studies. Clinical Pharmacokinetics, 42, 153-178.
http://dx.doi.org/10.2165/00003088-200342020-00004
[47] Erlank, H., Elmann, A., Kohen, R. and Kanner, J. (2011) Polyphenols Activate Nrf2 in Astrocytes via H2O2, Semiquinones, and Quinones. Free Radical Biology and Medicine, 51, 2319-2327.
http://dx.doi.org/10.1016/j.freeradbiomed.2011.09.033
[48] Rubiolo, J.A., Mithieux, G. and Vega, F.V. (2008) Resveratrol Protects Primary Rat Hepatocytes against Oxidative Stress Damage: Activation of the Nrf2 Transcription Factor and Augmented Activities of Antioxidant Enzymes. European Journal of Pharmacology, 591, 66-72. http://dx.doi.org/10.1016/j.ejphar.2008.06.067
[49] D’Autreaux, B. and Toledano, M.B. (2007) ROS as Signalling Molecules: Mechanisms That Generate Specificity in ROS Homeostasis. Nature Reviews Molecular Cell Biology, 8, 813-324. http://dx.doi.org/10.1038/nrm2256

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