Login Register Cart 0
Generic placeholder image

The Natural Products Journal

Editor-in-Chief

ISSN (Print): 2210-3155
ISSN (Online): 2210-3163

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Modulatory Effects of Mangiferin Isolated from Aquilaria Plants on Human Cytochrome P450 Enzyme (CYP) Activities In vitro and In silico Studies

Author(s): Yan Pan*, Premika Jagadish, Ung Yee Tze, Sharoen Lim Yu Ming, Lim Kuan Hon, Jason Loo Siau Ee, Yuh Fen Pung, Lamia Noushin Sadeque Chowdhury and Shang Tao

Volume 13, Issue 8, 2023

Published on: 07 April, 2023

Article ID: e070323214440 Pages: 10

DOI: 10.2174/2210315513666230307115348

Price: $65

Abstract

Background: Mangiferin has been identified as one of the major active constituents of Aquilaria plants. It was reported to have several promising chemotherapeutic potentials. Our preliminary data suggested that Aquilaria plant water extracts inhibited several cytochrome P450 (CYP) isoenzymes in vitro.

Objective: This study aimed to investigate the modulatory effects of mangiferin on six major drug metabolizing CYP enzymes including CYP2A6, CYP2B6, CYP2C9, CYP2D6, CYP3A4, and CYP3A5.

Methods: The enzyme activities were measured using fluorescence-based assays and enzyme kinetic such as IC50 parameters and Ki values were calculated to evaluate inhibitory potencies and mechanisms. Moreover, for potent inhibitions, molecular docking studies were carried out to explore potential interactions of residues between mangiferin and CYP enzymes.

Results: Our findings suggested that mangiferin could inhibit CYP2D6, CYP3A4, and CYP3A5 in vitro with IC50 values of 9.2, 8.7, and 4.3 μM, and Ki values of 3.8, 10.8, and 9.6 μM, in a non-competitive inhibition pattern. Molecular docking studies using AutoDock 4.2 identified potential residues contained in mangiferin that interacted with CYP2D6, CYP3A4, and CYP3A5, resulting in the observed inhibitory effects.

Conclusion: Mangiferin should be used carefully, in particular, with conventional drugs metabolized mainly by CYP2D6, CYP3A4, and CYP3A5. Further in vivo studies are recommended to evaluate the clinical relevance of these inhibitions.

Graphical Abstract

[1]
Ekor, M. The growing use of herbal medicines: Issues relating to adverse reactions and challenges in monitoring safety. Front. Pharmacol., 2014, 4(1), 177.
[http://dx.doi.org/10.3389/fphar.2013.00177] [PMID: 24454289]
[2]
Izzo, A.A. Interactions between herbs and conventional drugs: Overview of the clinical data. Med. Princ. Pract., 2012, 21(5), 404-428.
[http://dx.doi.org/10.1159/000334488] [PMID: 22236736]
[3]
Ondieki, G.; Nyagblordzro, M.; Kikete, S.; Liang, R.; Wang, L.; He, X. Cytochrome P450 and P-glycoprotein-mediated interactions involving african herbs indicated for common noncommunicable diseases. Evidence-based Complement. Altern. Med., 2017, 2017, 2582463.
[http://dx.doi.org/10.1155/2017/2582463] [PMID: 28250793]
[4]
Pan, Y.; Abd-Rashid, B.A.; Ismail, Z.; Ismail, R.; Mak, J.W.; Pook, P.C.K.; Er, H.M.; Ong, C.E. In vitro effects of active constituents and extracts of Orthosiphon stamineus on the activities of three major human cDNA-expressed cytochrome P450 enzymes. Chem. Biol. Interact., 2011, 190(1), 1-8.
[http://dx.doi.org/10.1016/j.cbi.2011.01.022] [PMID: 21276781]
[5]
Zanger, U.M.; Schwab, M. Cytochrome P450 enzymes in drug metabolism: Regulation of gene expression, enzyme activities, and impact of genetic variation. Pharmacol. Ther., 2013, 138(1), 103-141.
[http://dx.doi.org/10.1016/j.pharmthera.2012.12.007] [PMID: 23333322]
[6]
Hashim, Y.Z.H.Y.; Kerr, P.G.; Abbas, P.; Mohd Salleh, H. Aquilaria spp. (agarwood) as source of health beneficial compounds: A review of traditional use, phytochemistry and pharmacology. J. Ethnopharmacol., 2016, 189, 331-360.
[http://dx.doi.org/10.1016/j.jep.2016.06.055] [PMID: 27343768]
[7]
Adam, A.Z.; Lee, S.Y.; Mohamed, R. Pharmacological properties of agarwood tea derived from Aquilaria (Thymelaeaceae) leaves: An emerging contemporary herbal drink. J. Herb. Med., 2017, 10, 37-44.
[http://dx.doi.org/10.1016/j.hermed.2017.06.002]
[8]
Kuo, P.C.; Li, Y.C.; Yang, M.L.; Tzen, J.T.C. A feasible UHPLC‐MS/MS method for concurrent quantification of 10 bioactive principles in Aquilaria leaf tea by the multiple reaction monitoring analytical mode. Phytochem. Anal., 2020, 31(5), 583-593.
[http://dx.doi.org/10.1002/pca.2923] [PMID: 31990133]
[9]
Imran, M.; Arshad, M.S.; Butt, M.S.; Kwon, J.H.; Arshad, M.U.; Sultan, M.T. Mangiferin: A natural miracle bioactive compound against lifestyle related disorders. Lipids Health Dis., 2017, 16(1), 84.
[http://dx.doi.org/10.1186/s12944-017-0449-y] [PMID: 28464819]
[10]
Kakino, M.; Hara, H. Pharmacological Effects of Aquilaria Spp. In: Agarwood- Science Behind the Fragrance; Mohamed, R., Ed.; Springer Science, Berlin, Germany, 2016; pp. 125-136.
[http://dx.doi.org/10.1007/978-981-10-0833-7_8]
[11]
Rodeiro, I.; José Gómez-Lechón, M.; Perez, G.; Hernandez, I.; Herrera, J.A.; Delgado, R.; Castell, J.V.; Teresa Donato, M. Mangifera indica L. extract and mangiferin modulate cytochrome P450 and UDP-glucuronosyltransferase enzymes in primary cultures of human hepatocytes. Phytother. Res., 2013, 27(5), 745-752.
[http://dx.doi.org/10.1002/ptr.4782] [PMID: 22815239]
[12]
Rodeiro, I.; Donato, M.T.; Lahoz, A.; González-Lavaut, J.A.; Laguna, A.; Castell, J.V.; Delgado, R.; Gómez-Lechón, M.J. Modulation of P450 enzymes by Cuban natural products rich in polyphenolic compounds in rat hepatocytes. Chem. Biol. Interact., 2008, 172(1), 1-10.
[http://dx.doi.org/10.1016/j.cbi.2007.10.004] [PMID: 18053976]
[13]
Rodeiro, I.; Donato, M.T.; Jimenez, N.; Garrido, G.; Molina-Torres, J.; Menendez, R.; Castell, J.V.; Gómez-Lechón, M.J. Inhibition of human P450 enzymes by natural extracts used in traditional medicine. Phytother. Res., 2009, 23(2), 279-282.
[http://dx.doi.org/10.1002/ptr.2613] [PMID: 18844254]
[14]
Yan, P.; Tze, U.Y.; Jagadish, P.A.P.R.; Hon, L.K.; Chowdhury, L.N.S.; Tao, S.; Eng, O.C. In vitro inhibitory effects of agarwood tea (Aquilaria malaccensis Lamk) aqueous extract on human cytochrome P450 (CYP) enzyme activities. Drug Metab Bioanal Lett, 2022, 15(3), 178-191.
[http://dx.doi.org/10.2174/1872312815666220707114744] [PMID: 36508274]
[15]
Ngui, W.T.S. Isolation, identification and bioactivity evaluation of mangiferin and genkwanin 5-O-β-primeveroside in gaharu plant parts and finished products for Gaharu Technologies Sdn Bhd. Master thesis, University of Nottingham Malaysia: Semenyih, Aug 2018.
[16]
Ozgenc, A. Vivid® CYP450 Screening Kits User Guide. 2018. Available from: www.lifetechnologies.com
[17]
de Ron, L.; Rajaraman, G. Assessment of the time-dependent inhibition (TDI) potential of test compounds with human liver microsomes by IC50 shift method using a nondilution approach. Curr Protoc Pharmacol., 2012, Chapter 7:Unit 7.14
[http://dx.doi.org/10.1002/0471141755.ph0714s58] [PMID: 22948851]
[18]
Parkinson, A.; Kazmi, F.; Buckley, D.B.; Yerino, P.; Paris, B.L.; Holsapple, J.; Toren, P.; Otradovec, S.M.; Ogilvie, B.W. An evaluation of the dilution method for identifying metabolism-dependent inhibitors of cytochrome P450 enzymes. Drug Metab. Dispos., 2011, 39(8), 1370-1387.
[http://dx.doi.org/10.1124/dmd.111.038596] [PMID: 21525169]
[19]
Berman, H.M.; Westbrook, J.; Feng, Z.; Gilliland, G.; Bhat, T.N.; Weissig, H.; Shindyalov, I.N.; Bourne, P.E. The protein data bank. Nucleic Acids Res., 2000, 28(1), 235-242.
[http://dx.doi.org/10.1093/nar/28.1.235] [PMID: 10592235]
[20]
O’Boyle, N.M.; Banck, M.; James, C.A.; Morley, C.; Vandermeersch, T.; Hutchison, G.R. Open babel: An open chemical toolbox. J. Cheminform., 2011, 3(33), 1-14.
[21]
Morris, G.M.; Huey, R.; Lindstrom, W.; Sanner, M.F.; Belew, R.K.; Goodsell, D.S.; Olson, A.J. AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility. J. Comput. Chem., 2009, 30(16), 2785-2791.
[http://dx.doi.org/10.1002/jcc.21256] [PMID: 19399780]
[22]
Mittal, S.; Iqubal, M.K.; Iqbal, B.; Gupta, M.M.; Ali, J.; Baboota, S. A pervasive scientific overview on mangiferin in the prevention and treatment of various diseases with preclinical and clinical updates. J. Complement. Integr. Med., 2021, 18(1), 9-21.
[http://dx.doi.org/10.1515/jcim-2019-0250] [PMID: 32427121]
[23]
Du, S.; Liu, H.; Lei, T.; Xie, X.; Wang, H.; He, X.; Tong, R.; Wang, Y. Mangiferin: An effective therapeutic agent against several disorders. Mol. Med. Rep., 2018, 18(6), 4775-4786.
[http://dx.doi.org/10.3892/mmr.2018.9529] [PMID: 30280187]
[24]
Lu, H.; Gui, Y.; Zheng, L.; Liu, X. Morphological, crystalline, thermal and physicochemical properties of cellulose nanocrystals obtained from sweet potato residue. Food Res. Int., 2013, 50(1), 121-128.
[http://dx.doi.org/10.1016/j.foodres.2012.10.013]
[25]
Gu, P.C.; Wang, L.; Han, M.N.; Peng, J.; Shang, J.C.; Pan, Y.Q.; Han, W.L. Comparative pharmacokinetic study of mangiferin in normal and alloxan-induced diabetic rats after oral and intravenous administration by UPLC-MS/MS. Pharmacology, 2019, 103(1-2), 30-37.
[http://dx.doi.org/10.1159/000493364] [PMID: 30359985]
[26]
Wang, Z.; Deng, J.; Wang, Q.; Li, X.; Wei, H. Improvement in the solubility ofmangiferin by HP-b-CD inclusion. Chinese Tradit. Pat. Med., 2008, 30, 1123-1126.
[27]
Gelabert-Rebato, M.; Wiebe, J.C.; Martin-Rincon, M.; Galvan-Alvarez, V.; Curtelin, D.; Perez-Valera, M.; Habib, J.J.; Pérez-López, A.; Vega, T.; Morales-Alamo, D.; Calbet, J.A.L. Enhancement of exercise performance by 48 hours, and 15-day supplementation with mangiferin and Luteolin in men. Nutrients, 2019, 11(2), 344.
[http://dx.doi.org/10.3390/nu11020344] [PMID: 30736383]
[28]
Martignoni, M.; Groothuis, G.M.M.; de Kanter, R. Species differences between mouse, rat, dog, monkey and human CYP-mediated drug metabolism, inhibition and induction. Expert Opin. Drug Metab. Toxicol., 2006, 2(6), 875-894.
[http://dx.doi.org/10.1517/17425255.2.6.875] [PMID: 17125407]
[29]
Brandon, E.F.A.; Raap, C.D.; Meijerman, I.; Beijnen, J.H.; Schellens, J.H.M. An update on in vitro test methods in human hepatic drug biotransformation research: Pros and cons. Toxicol. Appl. Pharmacol., 2003, 189(3), 233-246.
[http://dx.doi.org/10.1016/S0041-008X(03)00128-5] [PMID: 12791308]
[30]
Rodeiro, I.; Hernandez, S.; Morffi, J.; Herrera, J.A.; Gómez-Lechón, M.J.; Delgado, R.; Espinosa-Aguirre, J.J. Evaluation of genotoxicity and DNA protective effects of mangiferin, a glucosylxanthone isolated from Mangifera indica L. stem bark extract. Food Chem. Toxicol., 2012, 50(9), 3360-3366.
[http://dx.doi.org/10.1016/j.fct.2012.06.032] [PMID: 22749943]
[31]
Li, H.; Wu, C.; Liu, Y.; Zhang, S.; Gao, X. Baihe Zhimu formula attenuates the efficacy of tamoxifen against breast cancer in mice through modulation of CYP450 enzymes. BMC Complement. Altern. Med., 2019, 19(1), 240.
[http://dx.doi.org/10.1186/s12906-019-2651-0] [PMID: 31484532]
[32]
Turpeinen, M.; Korhonen, L.E.; Tolonen, A.; Uusitalo, J.; Juvonen, R.; Raunio, H.; Pelkonen, O. Cytochrome P450 (CYP) inhibition screening: Comparison of three tests. Eur. J. Pharm. Sci., 2006, 29(2), 130-138.
[http://dx.doi.org/10.1016/j.ejps.2006.06.005] [PMID: 16890411]
[33]
Guideline on the Investigation of Drug Interactions; European Medicines Agency, 2012.
[34]
Hou, S.; Wang, F.; Li, Y.; Li, Y.; Wang, M.; Sun, D.; Sun, C. Pharmacokinetic study of mangiferin in human plasma after oral administration. Food Chem., 2011, 132(1), 289-294.
[http://dx.doi.org/10.1016/j.foodchem.2011.10.079] [PMID: 26434292]
[35]
Han, D.; Chen, C.; Zhang, C.; Zhang, Y.; Tang, X. Determination of mangiferin in rat plasma by liquid–liquid extraction with UPLC–MS/MS. J. Pharm. Biomed. Anal., 2010, 51(1), 260-263.
[http://dx.doi.org/10.1016/j.jpba.2009.07.021] [PMID: 19699046]
[36]
Liu, H.; Wang, K.; Tang, Y.; Sun, Z.; Jian, L.; Li, Z.; Wu, B.; Huang, C. Structure elucidation of in vivo and in vitro metabolites of mangiferin. J. Pharm. Biomed. Anal., 2011, 55(5), 1075-1082.
[http://dx.doi.org/10.1016/j.jpba.2011.03.012] [PMID: 21466941]
[37]
Fontana, E.; Dansette, P.; Poli, S.; Plan, C. Cytochrome P450 enzymes mechanism based inhibitors: Common sub-structures and reactivity. Curr. Drug Metab., 2005, 6(5), 413-451.
[http://dx.doi.org/10.2174/138920005774330639] [PMID: 16248836]
[38]
Fowler, S.; Zhang, H. In vitro evaluation of reversible and irreversible cytochrome P450 inhibition: Current status on methodologies and their utility for predicting drug-drug interactions. AAPS J., 2008, 10(2), 410-424.
[http://dx.doi.org/10.1208/s12248-008-9042-7] [PMID: 18686042]
[39]
Lisi, G.P.; Loria, J.P. Allostery in enzyme catalysis. Curr. Opin. Struct. Biol., 2017, 47, 123-130.
[http://dx.doi.org/10.1016/j.sbi.2017.08.002] [PMID: 28865247]
[40]
Fischer, A.; Smieško, M. A conserved allosteric site on drug-metabolizing CYPs: A systematic computational assessment. Int. J. Mol. Sci., 2021, 22(24), 13215.
[http://dx.doi.org/10.3390/ijms222413215] [PMID: 34948012]
[41]
Mo, S.L.; Liu, W.F.; Li, C.G.; Zhou, Z.W.; Luo, H.B.; Chew, H.; Liang, J.; Zhou, S.F. Pharmacophore, QSAR, and binding mode studies of substrates of human cytochrome P450 2D6 (CYP2D6) using molecular docking and virtual mutations and an application to chinese herbal medicine screening. Curr. Pharm. Biotechnol., 2012, 13(9), 1640-1704.
[http://dx.doi.org/10.2174/138920112800958779] [PMID: 22039821]
[42]
Dai, Z.R.; Ning, J.; Sun, G.B.; Wang, P.; Zhang, F.; Ma, H.Y.; Zou, L.W.; Hou, J.; Wu, J.J.; Ge, G.B.; Sun, X.B.; Yang, L. Cytochrome P450 3A enzymes are key contributors for hepatic metabolism of bufotalin, a natural constitute in chinese medicine chansu. Front. Pharmacol., 2019, 10(2), 52.
[http://dx.doi.org/10.3389/fphar.2019.00052] [PMID: 30778299]
[43]
Niwa, T.; Yasumura, M.; Murayama, N.; Yamazaki, H. Comparison of catalytic properties of cytochromes P450 3A4 and 3A5 by molecular docking simulation. Drug Metab. Lett., 2013, 8(1), 43-50.
[http://dx.doi.org/10.2174/1872312807666131229121228] [PMID: 24484539]
[44]
Hsu, M.H.; Johnson, E.F. Active-site differences between substrate-free and ritonavir-bound cytochrome P450 (CYP) 3A5 reveal plasticity differences between CYP3A5 and CYP3A4. J. Biol. Chem., 2019, 294(20), 8015-8022.
[http://dx.doi.org/10.1074/jbc.RA119.007928] [PMID: 30926609]
[45]
Jayakanthan, M.; Chandrasekar, S.; Muthukumaran, J.; Mathur, P.P. Analysis of CYP3A4-HIV-1 protease drugs interactions by computational methods for highly active antiretroviral therapy in HIV/AIDS. J. Mol. Graph. Model., 2010, 28(5), 455-463.
[http://dx.doi.org/10.1016/j.jmgm.2009.10.005] [PMID: 19931478]
[46]
Xue, Y.; Li, J.; Wu, Z.; Liu, G.; Tang, Y.; Li, W. Computational insights into the different catalytic activities of CYP 3A4 and CYP 3A5 toward schisantherin E. Chem. Biol. Drug Des., 2019, 93(5), 854-864.
[http://dx.doi.org/10.1111/cbdd.13475] [PMID: 30637977]
[47]
Pantsar, T.; Poso, A. Binding affinity via docking: Fact and fiction. Molecules, 2018, 23(8), 1899.
[http://dx.doi.org/10.3390/molecules23081899] [PMID: 30061498]
[48]
Taylor, C.; Crosby, I.; Yip, V.; Maguire, P.; Pirmohamed, M.; Turner, R.M. A review of the important role of CYP2D6 in pharmacogenomics. Genes, 2020, 11(11), 1295.
[http://dx.doi.org/10.3390/genes11111295] [PMID: 33143137]
[49]
Hicks, J.K.; Bishop, J.R.; Sangkuhl, K.; Müller, D.J.; Ji, Y.; Leckband, S.G.; Leeder, J.S.; Graham, R.L.; Chiulli, D.L. LLerena, A.; Skaar, T.C.; Scott, S.A.; Stingl, J.C.; Klein, T.E.; Caudle, K.E.; Gaedigk, A. Clinical pharmacogenetics implementation consortium (CPIC) guideline for CYP2D6 and CYP2C19 genotypes and dosing of selective serotonin reuptake inhibitors. Clin. Pharmacol. Ther., 2015, 98(2), 127-134.
[http://dx.doi.org/10.1002/cpt.147] [PMID: 25974703]
[50]
Yang, L.Q.; Li, S.J.; Cao, Y.F.; Man, X.B.; Yu, W.F.; Wang, H.Y.; Wu, M.C. Different alterations of cytochrome P450 3A4 isoform and its gene expression in livers of patients with chronic liver diseases. World J. Gastroenterol., 2003, 9(2), 359-363.
[http://dx.doi.org/10.3748/wjg.v9.i2.359] [PMID: 12532467]
[51]
Lynch, T.; Price, A. The effect of cytochrome P450 metabolism on drug response, interactions, and adverse effects. Am. Fam. Physician, 2007, 76(3), 391-396.
[PMID: 17708140]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy