Impact of Morus alba L. on the expression of drug-metabolizing enzymes and transporters in Caco-2 cells

Waranya Chatuphonprasert Wipawee Tukum-mee Jintanaporn Wattanathorn Kanokwan Jarukamjorn   

Open Access   

Published:  Jun 19, 2022

Abstract

Morus alba (MA) L. (mulberry) fruit has been consumed for a long time as a food and a source of vitamin C, anthocyanins, flavonoids, and alkaloids. The effects of MA fruit extract on drug-metabolizing genes and drug transporters were investigated in human colorectal adenocarcinoma cells. Cells treated with MA or its major bioactive constituents, rutin, and cyanidin-3-O-glucoside (C3G), were assessed for cell viability, production of reactive oxygen species (ROS), and alanine aminotransferase (ALT) and aspartate transaminase (AST) levels. The mRNA expression of target metabolic genes was determined using real-time polymerase chain reaction. Cell viability remained higher than 80%, and ROS levels were unchanged by all treatments. MA, C3G, and rutin did not alter the ALT and AST levels or expression of CYP2D6 and sulfotransferase 1A1 (SULT1A1). However, MA, C3G, and rutin down-regulated the expression of CYP2C19, CYP3A4, uridine diphosphate-glucuronosyltransferase 1A6 (UGT1A6), N-acetyltransferase 1, and organic anion transporting polypeptide 1B1 (OATP1B1), and MA elevated the expression of CYP1A2. In addition, MA induced CYP1A2 and CYP2C19 expression in combination with aspirin, caffeine, and simvastatin and upregulated expression of UGT1A6 and SULT1A1 in combination with paracetamol. Therefore, consumption of MA fruit or its supplements poses a risk for drug interactions via its modulation of cytochrome P450 and conjugation enzyme-associated metabolism and OATP1B1-mediated drug transport.


Keyword:     Mulberry cytochrome P450 rutin cyanidin-3-O-glucoside drug interaction.


Citation:

Chatuphonprasert W, Tukum-mee W, Wattanathorn J, Jarukamjorn K. Impact of Morus alba L. on the expression of drug-metabolizing enzymes and transporters in Caco-2 cells. J Appl Pharm Sci, 2022; 12(07):149–161.

Copyright: © The Author(s). This is an open-access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Reference

Abdulla MA, Ali HM, Ahmed KAA, Noor SM, Ismail S. Evaluation of the anti-ulcer activities of Morus alba extracts in experimentally-induced gastric ulcer in rats. Biomed Res, 2009; 20:35-9.

Alvin G, Catambay N, Vrgara A, Jamora MJ. A comparative study of the safety and efficacy of 75% mulberry (Morus alba) extract oil versus placebo as a topical treatment for melasma: a randomized, singleblind, placebo-controlled trial. J Drugs Dermatology, 2011; 10:1025-31.

Altemimi A, Lakhssassi N, Baharlouei A, Watson DG, Lightfoot DA. Phytochemicals: extraction, isolation, and identification of bioactive compounds from plant extracts. Plants, 2017; 6(4):42. https://doi.org/10.3390/plants6040042

Belayneh A, Molla F. The effect of coffee on pharmacokinetic properties of drugs: a review. BioMed Res Int, 2020; 2020;7909703. https://doi.org/10.1155/2020/7909703

Ben Sghaier M, Pagano A, Mousslim M, Ammari Y, Kovacic H, Luis J. Rutin inhibits proliferation, attenuates superoxide production and decreases adhesion and migration of human cancerous cells. Biomed Pharmacother, 2016; 84:1972-8. https://doi.org/10.1016/j.biopha.2016.11.001

Brück S, Strohmeier J, Busch D, Drozdzik M, Oswald S. Caco-2 cells - expression, regulation and function of drug transporters compared with human jejunal tissue. Biopharm Drug Dispos, 2017; 38:115-26. https://doi.org/10.1002/bdd.2025

Chan EWC, Lye PY, Wong SK. Phytochemistry, pharmacology, and clinical trials of Morus alba. Chin J Nat Med, 2016; 14:17-30.

Chang BY, Koo BS, Kim SY. Pharmacological activities for Morus alba L., focusing on the immunostimulatory property from the fruit aqueous extract. Foods, 2021; 10:1966. https://doi.org/10.3390/foods10081966

Chen C, Mohamad Razali UH, Saikim FH, Mahyudin A, Mohd Noor NQ. Morus alba L. plant: bioactive compounds and potential as a functional food ingredient. Foods, 2021; 10(3):689. https://doi.org/10.3390/foods10030689

Chen L, Liu L, Chen Y, Liu M, Xiong Y, Zhang H, Huang S, Xia C. Modulation of transporter activity of OATP1B1 and OATP1B3 by the major active components of Radix Ophiopogonis. Xenobiotica, 2019; 49:1221-8. https://doi.org/10.1080/00498254.2018.1493757

Choi MK, Jin QR, Choi YL, Ahn SH, Bae MA, Song IS. Inhibitory effects of ketoconazole and rifampin on OAT1 and OATP1B1 transport activities: considerations on drug-drug interactions. Biopharm Drug Dispos, 2011; 32:175-84. https://doi.org/10.1002/bdd.749

Choi YK, Cho SG, Choi HS, Woo SM, Yun YJ, Shin YC, Ko SG. JNK1/2 Activation by an extract from the roots of Morus alba L. reduces the viability of multidrug-resistant MCF-7/Dox cells by inhibiting YB-1- dependent MDR1 expression. Evid Based Complement Altern Med, 2013; 2013:741985. https://doi.org/10.1155/2013/741985

Chu Q, Lin M, Tian X, Ye J. Study on capillary electrophoresisamperometric detection profiles of different parts of Morus alba L. J Chromatogr A, 2006; 1116(1-2):286-90. https://doi.org/10.1016/j.chroma.2006.03.118

Darney K, Lautz LS, Béchaux C, Wiecek W, Testai E, Amzal B, Dorne JLCM. Human variability in polymorphic CYP2D6 metabolism: implications for the risk assessment of chemicals in food and emerging designer drugs. Environ Int, 2021; 156:106760. https://doi.org/10.1016/j.envint.2021.106760

Du QZ, Zheng J, Xu Y. Composition of anthocyanins in mulberry and their antioxidant activity. J Food Compos Anal, 2008; 21:390-5. https://doi.org/10.1016/j.jfca.2008.02.007

Fang HL, Strom SC, Ellis E, Duanmu Z, Fu J, DuniecDmuchowski Z, Falany CN, Falany JL, Kocarek TA, Runge-Morris M. Positive and negative regulation of human hepatic hydroxysteroid sulfotransferase (SULT2A1) gene transcription by rifampicin: roles of hepatocyte nuclear factor 4α and pregnane X receptor. J Pharmacol Exp Ther, 2007; 323:586-98. https://doi.org/10.1124/jpet.107.124610

Ferrari D, Speciale A, Cristani M, Fratantonio D, Molonia MS, Ranaldi G, Saija A, Cimino F. Cyanidin-3-O-glucoside inhibits NF-kB signalling in intestinal epithelial cells exposed to TNF-α and exerts protective effects via Nrf2 pathway activation. Toxicol Lett, 2016; 264:51-8. https://doi.org/10.1016/j.toxlet.2016.10.014

Fugh-Berman A. Herb-drug interactions. Lancet, 2000; 355:134-8. https://doi.org/10.1016/S0140-6736(99)06457-0

Gamage NU, Tsvetanov S, Duggleby RG, McManus ME, Martin JL. The structure of human SULT1A1 crystallized with estradiol: an insight into active site plasticity and substrate inhibition with multi-ring substrates. J Biol Chem, 2005; 280:41482-6. https://doi.org/10.1074/jbc.M508289200

Glaeser H, Drescher S, Eichelbaum M, Fromm MF. Influence of rifampicin on the expression and function of human intestinal cytochrome P450 enzymes. Br J Clin Pharmacol, 2005; 59:199-206. https://doi.org/10.1111/j.1365-2125.2004.02265.x

Gow JM, Hodges LM, Chinn LW, Kroetz DL. Substratedependent effects of human ABCB; coding polymorphisms. J Pharmacol Exp Ther, 2008; 325:435-42. https://doi.org/10.1124/jpet.107.135194

Gryn-Rynko A, Bazylak G, Olszewska-Slonina D. New potential phytotherapeutics obtained from white mulberry (Morus alba L.) leaves. Biomed Pharmacother, 2016; 84:628-36. https://doi.org/10.1016/j.biopha.2016.09.081

Hansawasdi C, Kawabata J. α-Glucosidase inhibitory effect of mulberry (Morus alba) leaves on Caco-2. Fitoterapia, 2006; 77(7-8):568-73. https://doi.org/10.1016/j.fitote.2006.09.003

Hunyadi A, Martins A, Hsieh TJ, Seres A, Zupkó I. Chlorogenic acid and rutin play a major role in the in vivo anti-diabetic activity of Morus alba leaf extract on type II diabetic rats. PLoS One, 2012; 7:e50619. https://doi.org/10.1371/journal.pone.0050619

Hussain F, Rana Z, Shafique H, Malik A, Hussain Z. Phytopharmacological potential of different species of Morus alba and their bioactive phytochemicals: a review. Asian Pac J Trop Biomed, 2017; 7(10):950-6. https://doi.org/10.1016/j.apjtb.2017.09.015

Iftikhar M, Iftikhar A, Zhang H, Gong L, Wang J. Transport, metabolism and remedial potential of functional food extracts (FFEs) in Caco-2 cells monolayer: A review. Food Res Int, 2020; 136:109240. https://doi.org/10.1016/j.foodres.2020.109240

Kar A, Mukherjee PK, Saha S, Bahadur S, Ahmmed SK, Pandit S. Possible herb-drug interaction of Morus alba L.-A potential anti-diabetic plant from Indian Traditional medicine. Indian J Trad Knowl, 2015; 14(4):626-31.

Kayesh R, Farasyn T, Crowe A, Liu Q, Pahwa S, Alam K, Neuhoff S, Hatley O, Ding K, Yue W. Assessing OATP1B1- and OATP1B3- mediated drug-drug interaction potential of vemurafenib using R-value and physiologically-based pharmacokinetic models. J Pharm Sci, 2021; 110:314-24. https://doi.org/10.1016/j.xphs.2020.06.016

Kellick KA, Bottorff M, Toth PP. A clinician's guide to statin drug-drug interactions. J Clin Lipid, 2014; 8(3):30-46. https://doi.org/10.1016/j.jacl.2014.02.010

Van de Kerkhof EG, de Graaf IAM, Ungell ALB, Groothuis GMM. induction of metabolism and transport in human intestine: validation of precision-cut slices as a tool to study induction of drug metabolism in human intestine in vitro. Drug Metab Dispos, 2008; 36:604-13. https://doi.org/10.1124/dmd.107.018820

Kim SB, Kim KS, Kim DD, Yoon IS. Metabolic interactions of rosmarinic acid with human cytochrome P450 monooxygenases and uridine diphosphate glucuronosyltransferases. Biomed Pharmacother, 2019; 110:111-7. https://doi.org/10.1016/j.biopha.2018.11.040

Kükürt A, Gelen V, Ba?er ÖF, Deveci HA, Karapehlivan M. Thiols: role in oxidative stress-related disorders. In: Atukeren P (ed.). Accenting lipid peroxidation. IntechOpen, London, UK, 2021. https://doi.org/10.5772/intechopen.96682

Kuncharoenwirat N, Chatuphonprasert W, Jarukamjorn K. Effects of phenol red on rifampicin-induced expression of cytochrome P450s enzymes. Pharmacophore, 2020; 11(3):13-20.

Li X, Zhao K, Ma N, Sun S, Miao Z, Zhao Z. Association of ABCB1 promoter methylation with aspirin exposure, platelet function, and clinical outcomes in Chinese intracranial artery stenosis patients. Eur J Clin Pharmacol, 2017; 73:1261-9. https://doi.org/10.1007/s00228-017-2298-z

Mei M, Ruan JQ, Wu WJ, Zhou RN, Lei JP, Zhao HY, Yan R, Wang YT. In vitro pharmacokinetic characterization of mulberroside A, the main polyhydroxylated stilbene in mulberry (Morus alba L.), and its bacterial metabolite oxyresveratrol in traditional oral use. J Agric Food Chem, 2012; 60(9):2299-308. https://doi.org/10.1021/jf204495t

Meszaros P, Hummel I, Klappe K, Draghiciu O, Hoekstra D, Kok JW. The function of the ATP-binding cassette (ABC) transporter ABCB1 is not susceptible to actin disruption. Biochim Biophys Acta - Biomembr, 2013; 1828:340-51. https://doi.org/10.1016/j.bbamem.2012.10.007

Netsch MI, Gutmann H, Schmidlin CB, Aydogan C, Drewe J. Induction of CYP1A by green tea extract in human intestinal cell lines. Planta Med, 2006; 72:514-20. https://doi.org/10.1055/s-2006-931537

Nikulin SV, Tonevitsky EA, Poloznikov AA. Effect of ketoconazole on the transport and metabolism of drugs in the human liver cell model. Russ Chem Bull, 2017; 66:150-5. https://doi.org/10.1007/s11172-017-1713-z

Novotna A, Korhonova M, Bartonkova I, Soshilov AA, Denison MS, Bogdanova K, Kolar M, Bedlar M, Dvorak Z. Enantiospecific effects of ketoconazole on aryl hydrocarbon receptor. PLoS One, 2014; 9:e101832. https://doi.org/10.1371/journal.pone.0101832

Pahwa S, Alam K, Crowe A, Farasyn T, Neuhoff S, Hatley O, Ding K, Yue W. Pretreatment with rifampicin and tyrosine kinase inhibitor dasatinib potentiates the inhibitory effects toward OATP1B1- and OATP1B3-Mediated Transport. J Pharm Sci, 2017; 106:2123-35. https://doi.org/10.1016/j.xphs.2017.03.022

Pandurangan M, Kim DH. ZnO nanoparticles augment ALT, AST, ALP and LDH expressions in C2C12 cells. Saudi J Biol Sci, 2015; 22:679-84. https://doi.org/10.1016/j.sjbs.2015.03.013

Park KT, Kim JK, Hwang D, Yoo Y, Lim YH. Inhibitory effect of mulberroside A and its derivatives on melanogenesis induced by ultraviolet B irradiation. Food Chem Toxicol, 2011; 49(12):3038-45. https://doi.org/10.1016/j.fct.2011.09.008

Rana R, Chen Y, Ferguson SS, Kissling GE, Surapureddi S, Goldstein JA. Hepatocyte nuclear factor 4α regulates rifampicin-mediated induction of CYP2C genes in primary cultures of human hepatocytes. Drug Metab Dispos, 2010; 38:591-9. https://doi.org/10.1124/dmd.109.030387

Rasool MI, Bairam AF, Gohal SA, El Daibani AA, Alherz FA, Abunnaja MS, Alatwi ES, Kurogi K, Liu M. Effects of the human SULT1A1 polymorphisms on the sulfation of acetaminophen, O-desmethylnaproxen, and tapentadol. Pharmacol Reports, 2019; 71:257-65. https://doi.org/10.1016/j.pharep.2018.12.001

Saxena A, Balaramnavar VM, Hohlfeld T, Saxena AK. Drug/ drug interaction of common NSAIDs with antiplatelet effect of aspirin in human platelets. Eur J Pharmacol, 2013; 721(1-3):215-24. https://doi.org/10.1016/j.ejphar.2013.09.032

Sepulveda JL. 2019. Chapter 10: Challenges in routine clinical chemistry analysis: proteins and enzymes. In: Dasgupta A, Sepulveda JL, ed. Accurate results in the clinical laboratory 2nd edition. New York: Elsevier 141-63. https://doi.org/10.1016/B978-0-12-813776-5.00010-8

Sheng C, Shi Xiaoyan, Ding Z, Chen Y, Shi Xiaoqian, Wu Y, Zhang W, Chen W. Effects of mulberry leaf extracts on activity and mRNA expression of five cytochrome P450 enzymes in rat. Brazilian J Pharm Sci, 2021; 57:e18059. https://doi.org/10.1590/s2175-97902020000x181059

Shi X, Yang S, Zhang G, Song Y, Su D, Liu Y, Guo F, Shan L, Cai J. The different metabolism of morusin in various species and its potent inhibition against UDP-glucuronosyltransferase (UGT) and cytochrome p450 (CYP450) enzymes. Xenobiotica, 2016; 46:467-76. https://doi.org/10.3109/00498254.2015.1086839

Sorf A, Hofman J, Ku?era R, Staud F, Ceckova M. Ribociclib shows potential for pharmacokinetic drug-drug interactions being a substrate of ABCB1 and potent inhibitor of ABCB1, ABCG2 and CYP450 isoforms in vitro. Biochem Pharmacol, 2018; 154:10-7. https://doi.org/10.1016/j.bcp.2018.04.013

Sousa MC, Braga RC, Cintra BAS, de Oliveira V, Andrade CH. In silico metabolism studies of dietary flavonoids by CYP1A2 and CYP2C9. Food Res Int, 2013; 50:102-10. https://doi.org/10.1016/j.foodres.2012.09.027

Sriset Y, Chatuphonprasert W, Jarukamjorn K. Bergenin attenuates sodium selenite-induced hepatotoxicity via improvement of hepatic oxidant-antioxidant balance in HepG2 cells and ICR mice. J Biol Act Prod from Nat, 2021; 11:97-115. https://doi.org/10.1080/22311866.2021.1908162

Srovnalova A, Svecarova M, Kopecna Zapletalova M, Anzenbacher P, Bachleda P, Anzenbacherova E, Dvorak Z. Effects of anthocyanidins and anthocyanins on the expression and catalytic activities of CYP2A6, CYP2B6, CYP2C9, and CYP3A4 in primary human hepatocytes and human liver microsomes. J Agric Food Chem, 2014; 62:789-97. https://doi.org/10.1021/jf404643w

Sun H, Lou XY, Wu XY, Wang H, Qu Q, Tan SL, Ruan JS, Qu J, Chen H. Up-regulation of CYP2C19 expression by BuChang NaoXinTong via PXR activation in HepG2 cells. PLoS One, 2016; 11:e0160285. https://doi.org/10.1371/journal.pone.0160285

Takano M, Hasegawa R, Fukuda T, Yumoto R, Nagai J, Murakami T. Interaction with P-glycoprotein and transport of erythromycin, midazolam and ketoconazole in Caco-2 cells. Eur J Pharmacol, 1998; 358:289-94. https://doi.org/10.1016/S0014-2999(98)00607-4

Toes MJ, Jones AL, Prescott L. Drug interactions with paracetamol. Am J Ther, 2005; 12(1):56-66. https://doi.org/10.1097/00045391-200501000-00009

Udomsak W, Chatuphonprasert W, Jarukamjorn K. Dill shows potential for herb-drug interactions via up-regulation of CYP1A2, CYP2C19, SULT1A1, NAT2 and ABCB1 in Caco-2 Cells. Pakistan J Biol Sci, 2022; 25(1):56-66. https://doi.org/10.3923/pjbs.2022.56.66

Uppugunduri RS, Daali Y, Desmeules J, Dayer P, Krajinovic M, Ansari M. Transcriptional regulation of CYP2C19 and its role in altered enzyme activity. Curr Drug Metab, 2012; 13:1196-204. https://doi.org/10.2174/138920012802850146

Vaessen SFC, van Lipzig MMH, Pieters RHH, Krul CAM, Wortelboer HM, van de Steeg E. Regional expression levels of drug transporters and metabolizing enzymes along the pig and human intestinal tract and comparison with Caco-2 cells. Drug Metab Dispos, 2017; 45:353-60. https://doi.org/10.1124/dmd.116.072231

Walker K, Ginsberg G, Hattis D, Johns DO, Guyton KZ, Sonawane B. Genetic polymorphism in N-acetyltransferase (NAT): population distribution of NAT1 and NAT2 activity. J Toxicol Environ Heal Part B, 2009; 12:440-72. https://doi.org/10.1080/10937400903158383

Walter Bock K, Köhle C. UDP-glucuronosyltransferase 1A6: structural, functional, and regulatory aspects-Phase II conjugation enzyme and transportataion system. Method Enzymol, 2005; 400:57-75. https://doi.org/10.1016/S0076-6879(05)00004-2

Wang X, Wolkoff AW, Morris ME. Flavonoids as a novel class of human organic anion-transporting polypeptide OATP1B1 (OATP-C) modulators. Drug Metab Dispos, 2005; 33:1666-72. https://doi.org/10.1124/dmd.105.005926

Witham KL, Minchin RF, Butcher NJ. Role for human arylamine N-acetyltransferase 1 in the methionine salvage pathway. Biochem Pharmacol, 2017; 125:93-100. https://doi.org/10.1016/j.bcp.2016.11.015

Zafar MS, Muhammad F, Javed I, Akhtar M, Khaliq T, Aslam B, Waheed A, Yasmin R, Zafar H. White mulberry (Morus alba): a brief phytochemical and pharmacological evaluations account. Int J Agric Biol, 2013; 15(3):612-20.

Zanger UM, Schwab M. Cytochrome P450 enzymes in drug metabolism: regulation of gene expression, enzyme activities, and impact of genetic variation. Pharmacol Ther, 2013; 138:103-41. https://doi.org/10.1016/j.pharmthera.2012.12.007

Zhang H, Ma ZF, Luo X, Li X. Effects of mulberry fruit (Morus alba L.) consumption on health outcomes: a mini-review. Antioxidants, 2018; 7:69. https://doi.org/10.3390/antiox7050069

Zhang W, He YJ, Gan Z, Fan L, Li Q, Wang A, Liu ZQ, Deng S, Huang YF, Xu LY, Zhou HH. OATP1B1 polymorphism is a major determinant of serum bilirubin level but not associated with rifampicin-mediated bilirubin elevation. Clin Exp Pharmacol Physiol, 2007; 34:1240-4. https://doi.org/10.1111/j.1440-1681.2007.04798.x

Zhang X, Song J, Shi X, Miao S, Li Y, Wen A. Absorption and metabolism characteristics of rutin in Caco-2 cells. Sci World J, 2013; 2013:382350. https://doi.org/10.1155/2013/382350

Zhao L, Pickering G. Paracetamol metabolism and related genetic differences. Drug Metab Rev, 2011; 43:41-52. https://doi.org/10.3109/03602532.2010.527984

Zhao S, Park CH, Li X, Kim YB, Yang J, Sung GB, Park NI, Kim S, Park SU. Accumulation of rutin and betulinic acid and expression of phenylpropanoid and triterpenoid biosynthetic genes in mulberry (Morus alba L.). J Agric Food Chem, 2015; 63:8622-30. https://doi.org/10.1021/acs.jafc.5b03221

Zhou SF, Wang B, Yang LP, Liu JP. Structure, function, regulation and polymorphism and the clinical significance of human cytochrome P450 1A2. Drug Metab Rev, 2010; 42:268-354. https://doi.org/10.3109/03602530903286476

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