Mulberry (Morus alba L.): Risk of herb–drug interactions via alteration of phase I and II metabolizing enzymes and transporters in HepG2 cells

Wachirawit Udomsak Waranya Chatuphonprasert Wipawee Tukum-mee Jintanaporn Wattanathorn Kanokwan Jarukamjorn   

Open Access   

Published:  Sep 04, 2022

DOI: 10.7324/JAPS.2022.121202
Abstract

Mulberry (Morus alba Linn; MA) is a food supplement that may cause herb–drug interactions (HDIs). Potential interactions of MA, its constituents cyanidin 3-glucoside (C3G) and rutin, and four common pharmacologically active agents were examined in HepG2 cells. Cells were incubated with 1–10 μM C3G, 1–10 μM rutin, and 125–500 μg/ ml MA alone and in combination with 5 mM acetaminophen (APAP), 5 mM aspirin (ASA), 10 μM simvastatin (SV), or 50 μM caffeine (CF) for 72 hours. The expressions of phase I and II metabolizing enzymes and transporters were determined by RT/qPCR. When tested alone, MA significantly upregulated the expression of CYP1A2 and UDP-glucuronosyltransferase 1A6 (UGT1A6). Cotreatment of HepG2 cells with APAP, ASA, SV, or CF, and MA resulted in upregulation of CYP1A2 and N-acetyltransferase 1 expression and downregulation of ATP-binding cassette B1 and solute carrier organic anion 1B1 expression. Combining MA with APAP, ASA, or SV elevated CYP2C19 expression, and MA and ASA coinduced the expression of CYP2D6. Coadministration of MA with APAP or ASA increased UGT1A6 expression. C3G and rutin did not affect the expression of any tested genes. Consequently, MA is recommended to be taken at a low dosage due to the feasibility of MA HDIs arising from concomitant use with APAP, ASA, SV, or caffeine.


Keyword:     Rutin cyanidin 3-glucoside metabolizing enzyme herb–drug interaction cytochrome P450 transporter


Citation:

Udomsak W, Chatuphonprasert W, Tukum-mee W, Wattanathorn J, Jarukamjorn K. Mulberry (Morus alba L.): Risk of herb–drug interactions via alteration of phase I and II metabolizing enzymes and transporters in HepG2 cells. J Appl Pharm Sci, 2022; https://doi.org/10.7324/JAPS.2022.121202

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.

HTML Full Text

Reference

Aninat C, Piton A, Glaise D, Le Charpentier T, Langouët S, Morel F, Guguen-Guillouzo C, Guillouzo A. Expression of cytochromes P450, conjugating enzymes and nuclear receptors in human hepatoma HepaRG cells. Drug Metab Dispos, 2006; 34(1):75-83; doi:10.1124/ dmd.105.006759 https://doi.org/10.1124/dmd.105.006759

Bae SH, Suh HJ. Antioxidant activities of five different mulberry cultivars in Korea. LWT Food Sci Technol, 2007; 40(6):955-62; doi:10.1016/j.lwt.2006.06.007 https://doi.org/10.1016/j.lwt.2006.06.007

Belayneh A, Molla F. The effect of coffee on pharmacokinetic properties of drugs: a review. BioMed Res Int, 2020; 2020:1-11; doi:10.1155/2020/7909703 https://doi.org/10.1155/2020/7909703

Bhuiyan MIH, Kim HB, Kim SY, Cho KO. The neuroprotective potential of cyanidin-3-glucoside fraction extracted from mulberry following oxygen-glucose deprivation. Korean J Physiol Pharmacol, 2011; 15(6):353-61; doi:10.4196/kjpp.2011.15.6.353 https://doi.org/10.4196/kjpp.2011.15.6.353

Carrillo JA, Benitez J. Clinically significant pharmacokinetic interactions between dietary caffeine and medications. Clin Pharmacokinet, 2000; 39(2):127-53; doi:10.2165/00003088-200039020-00004 https://doi.org/10.2165/00003088-200039020-00004

Chatuphonprasert W, Kitisripanya T, Putalun W, Ellinger I, Jarukamjorn K. Pueraria candollei var. mirifica-induced CYP1A1 and CYP1A2 expression in human choriocarcinoma BeWo cells. Pharmacogn Magaz, 2020; 16(5):506-12; doi:10.4103/pm.pm https://doi.org/10.4103/pm.pm_164_20

Chatuphonprasert W, Tatiya-aphiradee N, Jarukamjorn K. Effect of Plumbago indica Linn. and plumbagin on the expression of hepatic cytochrome P450 2e1 and lung cytochrome P450 2f2 in mice. J Sci Technol Mahasarakham Univ, 2015; 34(6):692-6.

Chen PN, Chu SC, Chiou HL, Kuo WH, Chiang CL, Hsieh YS. Mulberry anthocyanins, cyanidin 3-rutinoside and cyanidin 3-glucoside, exhibited an inhibitory effect on the migration and invasion of a human lung cancer cell line. Cancer Lett, 2006; 235(2):248-59; doi:10.1016/j. canlet.2005.04.033 https://doi.org/10.1016/j.canlet.2005.04.033

Chen XP, Tan ZR, Huang SL, Huang Z, Ou-Yang DS, Zhou HH. Isozyme-specific induction of low-dose aspirin on cytochrome P450 in healthy subjects. Clin Pharmacol Therap, 2003; 73(3):264-71; doi:10.1067/ mcp.2003.14 https://doi.org/10.1067/mcp.2003.14

Estudante M, Morais JG, Soveral G, Benet LZ. Intestinal drug transporters: an overview. Adv Drug Deliv Rev, 2013; 65(10):1340-56; doi:10.1016/j.addr.2012.09.042 https://doi.org/10.1016/j.addr.2012.09.042

Fagerberg L, Hallstrom BM, Oksvold P, Kampf C, Djureinovic D, Odeberg J, Habuka M, Tahmasebpoor S, Danielsson A, Edlund K, Asplund A, Sjostedt E, Lundberg E, Szigyarto CAK, Skogs M, Ottosson Takanen J, Berling H, Tegel H, Mulder J, Nilsson P, Schwenk JM, Lindskog C, Danielsson F, Mardinoglu A, Sivertsson A, von Feilitzen K, Forsberg M, Zwahlen M, Olsson I, Navani S, Huss M, Nielsen J, Ponten F, Uhlen M. Analysis of the human tissue-specific expression by genome-wide integration of transcriptomics and antibody-based proteomics. Mol Cell Proteomics, 2014; 13(2):397-406; doi:10.1074/mcp.M113.035600 https://doi.org/10.1074/mcp.M113.035600

Gerets HHJ, Tilmant K, Gerin B, Chanteux H, Depelchin BO, Dhalluin S, Atienzar FA. Characterization of primary human hepatocytes, HepG2 cells, and HepaRG cells at the mRNA level and CYP activity in response to inducers and their predictivity for the detection of human hepatotoxins. Cell Biol Toxicol, 2012; 28(2):69-87; doi:10.1007/s10565-011-9208-4 https://doi.org/10.1007/s10565-011-9208-4

Go RE, Hwang KA, Choi KC. Cytochrome P450 1 family and cancers. J Steroid Biochem Mol Biol, 2015; 147:24-30; doi:10.1016/j. jsbmb.2014.11.003 https://doi.org/10.1016/j.jsbmb.2014.11.003

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(11):7-12; doi:10.1371/journal.pone.0050619 https://doi.org/10.1371/journal.pone.0050619

Ittaman SV, VanWormer JJ, Rezkalla SH. The role of aspirin in the prevention of cardiovascular disease. Clin Med Res, 2014; 12(3- 4):147-54; doi:10.3121/cmr.2013.1197 https://doi.org/10.3121/cmr.2013.1197

Jin S M, Park K. Acetaminophen induced cytotoxicity and altered gene expression in cultured cardiomyocytes of H9C2 cells. Environ Health Toxicol, 2012; 27:1-8; doi:10.5620/eht.2012.27.e2012011 https://doi.org/10.5620/eht.2012.27.e2012011

Kang P, Dalvie D, Smith E, Zhou S, Deese A, Nieman JA. Bioactivation of flutamide metabolites by human liver microsomes. Drug Metab Dispos, 2008; 36(7):1425-37; doi:10.1124/dmd.108.020370 https://doi.org/10.1124/dmd.108.020370

Kawamura A, Graham J, Mushtaq A, Tsiftsoglou SA, Vath GM, Hanna PE, Wagner CR, Sim E. Eukaryotic arylamine N-acetyltransferase. Investigation of substrate specificity by high-throughput screening. Biochem Pharmacol, 2005; 69(2):347-59. https://doi.org/10.1016/j.bcp.2004.09.014

Kiang TKL, Ensom MHH, Chang TKH. UDP-glucuronosyltransferases and clinical drug-drug interactions. Pharmacol Therap, 2005; 106(1):97-132; doi:10.1016/j.pharmthera.2004.10.013 https://doi.org/10.1016/j.pharmthera.2004.10.013

Miners JO. Drug interactions involving aspirin (acetylsalicylic acid) and salicylic acid. Clin Pharmacokin, 1989; 17(5):327-44; doi:10.2165/00003088-198917050-00003 https://doi.org/10.2165/00003088-198917050-00003

Nakanishi T, Tamai I. Genetic polymorphisms of OATP transporters and their impact on intestinal absorption and hepatic disposition of drugs. Drug Metab Pharmacokin, 2012; 27(1):106-21; doi:10.2133/ dmpk.dmpk-11-rv-099 https://doi.org/10.2133/dmpk.DMPK-11-RV-099

Nebert DW, Dalton TP. The role of cytochrome P450 enzymes in endogenous signalling pathways and environmental carcinogenesis. Nat Rev Cancer, 2006; 6(12):947-60; doi:10.1038/nrc2015 https://doi.org/10.1038/nrc2015

Meyer UA. Overview of enzymes of drug metabolism. J Pharmacokin Biopharma, 1996; 24(5):449-59; doi:10.1007/BF02353473 https://doi.org/10.1007/BF02353473

Prueksaritanont T, Ma B, Yu N. The human hepatic metabolism of simvastatin hydroxy acid is mediated primarily by CYP3A, and not CYP2D6. Br J Clin Pharmacol, 2003; 56(1):120-4; doi:10.1046/j.1365- 2125.2003.01833.x https://doi.org/10.1046/j.1365-2125.2003.01833.x

Sharom FJ. ABC multidrug transporters : structure, function and role in chemoresistance. Pharmacogenomics, 2008; 9(1):105-27; doi:10.2217/14622416.9.1.105 https://doi.org/10.2217/14622416.9.1.105

Sibbing D, Gebhard D, Koch W, Braun S, Stegherr J, Morath T, Von Beckerath N, Mehilli J, Schömig A, Schuster T, Kastrati A. Isolated and interactive impact of common CYP2C19 genetic variants on the antiplatelet effect of chronic clopidogrel therapy. J Thromb Haemost, 2010; 8(8):1685- 93; doi:10.1111/j.1538-7836.2010.03921.x https://doi.org/10.1111/j.1538-7836.2010.03921.x

Sim E, Abuhammad A, Ryan A. Arylamine N-acetyltransferases: from drug metabolism and pharmacogenetics to drug discovery. Br J Pharmacol, 2014; 171(11):2705-25; doi:10.1111/bph.12598Toes MJ, Jones AL, Prescott L. Drug interactions with paracetamol. Am J Therap, 2005; 12(1):56-66; doi:10.1097/00045391-200501000-00009 https://doi.org/10.1097/00045391-200501000-00009

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

Tolosa L, Gómez-Lechón MJ, López S, Guzmán C, Castell JV, Donato MT, Jover R. Human upcyte hepatocytes: characterization of the hepatic phenotype and evaluation for acute and long-term hepatotoxicity routine testing. Toxicol Sci, 2016; 152(1):214-29; doi:10.1093/toxsci/ kfw078 https://doi.org/10.1093/toxsci/kfw078

Walter Bock K, Köhle C. UDP-glucuronosyltransferase 1A6: structural, functional, and regulatory aspects. Meth Enzymol, 2005; 400(05):57-75; doi:10.1016/S0076-6879(05)00004-2Yang NC, Jhou KY, Tseng CY. Antihypertensive effect of mulberry leaf aqueous extract containing gamma-aminobutyric acid in spontaneously hypertensive rats. Food Chem, 2012; 132(4):1796-801; doi:10.1016/j.foodchem.2011.11.143 https://doi.org/10.1016/j.foodchem.2011.11.143

Zanger UM, Schwab M. Cytochrome P450 enzymes in drug metabolism: regulation of gene expression, enzyme activities, and impact of genetic variation. Pharmacol Therap, 2013; 138(1):103-41; doi:10.1016/j. pharmthera.2012.12.007 https://doi.org/10.1016/j.pharmthera.2012.12.007

Article Metrics

1 Absract views 0 PDF Downloads 1 Total views

   Abstract      Pdf Download

Related Search

By author names

Citiaion Alert By Google Scholar

Name Required
Email Required Invalid Email Address

Comment required