Oridonin, the major terpene found in Rabdosia rubescens, is widely used as a dietary supplement or therapeutic drug. However, the effects of oridonin on major CYP450s are still unclear. As oridonin can enhance the effect of other clinical drugs, in this study, we investigated the influence of oridonin on CYP450s mRNA expression and its impact on activities in human HepaRG cell to evaluate the safety by studying its potential drug interaction. HepaRG cells were cultured with series concentrations of oridonin (1, 5, 10, and 20 μmol/L), and the major CYP450s mRNA and protein expression, as well as enzyme activities were analyzed by real-time polymerase chain reaction, Western blot analysis and UPLC-MS/MS-based metabolite assay. In general, ordonin has induced effects on the major member of CYP450s mRNA and protein expression, as well as on the enzyme activity in human HepaRG cells, especially on CYP3A4 and CYP2C9. To our knowledge, this is the first systematic research about the inductive effects of oridonin on the major member of CYP450s in human cell line. These results may provide at least partly of the basis for potential drug-drug interactions and oridonin should be used with caution to avoid potential risk.

Keywords:
Oridonin, CYP450s, Diterpenoid, Drug-drug interaction
1.
Ding Y, Ding C, Ye N, Liu Z, Wold EA, Chen H, Wild C, Shen Q, Zhou J: Discovery and development of natural product oridonin-inspired anticancer agents. Eur J Med Chem 2016; 122: 102–117.
2.
Li D, Han T, Liao J, Hu X, Xu S, Tian K, Gu X, Cheng K, Li Z, Hua H, Xu J: Oridonin, a promising ent-kaurane diterpenoid lead compound. Int J Mol Sci 2016; 17:pii:E1395.
3.
Choi JG, Eom SM, Kim J, Kim SH, Huh E, Kim H, Lee Y, Lee H, Oh MS: A comprehensive review of recent studies on Herb-Drug interaction: a focus on pharmacodynamic interaction. J Altern Complement Med 2016; 22: 262–279.
4.
Ma BL, Ma YM: Pharmacokinetic herb-drug interactions with traditional Chinese medicine: progress, causes of conflicting results and suggestions for future research. Drug Metab Rev 2016; 48:1–26.
5.
Zanger UM, Turpeinen M, Klein K, Schwab M: Functional pharmacogenetics/genomics of human cytochromes P450 involved in drug biotransformation. Anal Bioanal Chem 2008; 392:1093–108.
6.
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.
7.
Bauer S, Störmer E, Johne A, Krüger H, Budde K, Neumayer HH, Roots I, Mai I: Alterations in cyclosporin a pharmacokinetics and metabolism during treatment with St John’s wort in renal transplant patients. Br J Clin Pharmacol 2002; 55: 203–211.
8.
Dresser GK, Schwarz UI, Wilkinson GR, Kim RB: Coordinate induction of both cytochrome P4503A and MDR1 by St John’s wort in healthy subjects. Clin Pharmacol Ther 2003; 73: 41–50.
9.
Hunter SR, Vonk A, Mullen Grey AK, Riddick DS: Role of glucocorticoid receptor and pregnane X receptor in dexamethasone induction of rat hepatic aryl hydrocarbon receptor nuclear translocator and NADPH-cytochrome P450 oxidoreductase. Drug Metab Dispos 2017; 45: 118–129.
10.
Zhang YW, Bao MH, Hu L, Qu Q, Zhou HH: Dose-response of oridonin on hepatic cytochromes P450 mRNA expression and activities in mice. J Ethnopharmacol 2014; 155: 714–720.
11.
Zhang YW, Bao MH, Wang G, Qu Q, Zhou HH: Induction of human CYP3A4 by huperzine A, ligustrazine and oridonin through pregnane X receptor-mediated pathways. Pharmazie 2014; 69: 532–536.
12.
Ngan CH, Beglov D, Rudnitskaya AN, Kozakov D, Waxman DJ, Vajda S: The structural basis of pregnane X receptor binding promiscuity. Biochemistry 2009; 48: 11572–11581.
13.
Lehmann JM, McKee DD, Watson MA, Willson TM, Moore JT, Kliewer SA: The human orphan nuclear receptor PXR is activated by compounds that regulate CYP3A4 gene expression and cause drug interactions. J Clin Invest 1998; 102:1016–1023.
14.
Guillouzo A, Corlu A, Aninat C, Glaise D, Morel F, Guguen-Guillouzo C: The human hepatoma HepaRG cells: a highly differentiated model for studies of liver metabolism and toxicity of xenobiotics. Chem Biol Interact 2007; 168:66–73.
15.
Antherieu S, Chesne C, Li R, Guguen-Guillouzo C, Guillouzo A: Optimization of the HepaRG cell model for drug metabolism and toxicity studies. Toxicol In Vitro 2012; 26: 1278–1285.
16.
Klein M, Thomas M, Hofmann U, Seehofer D, Damm G, Zanger UM: A systematic comparison of the impact of inflammatory signaling on absorption, distribution, metabolism, and excretion gene expression and activity in primary human hepatocytes and HepaRG cells. Drug Metab Dispos 2015; 43: 273–283.
17.
Chen Y, Cai S: Determination of human plasma protein binding rate of oridonin by ultrafiltration and high-performance liquid chromatography. China Med Herald 2013; 10: 25–27.
18.
Zheng H, Li J, Yao H: [Study on pharmacokinetics of oridonin in mice]. Zhongguo Zhong Yao Za Zhi 2011; 36: 3515–3518.
19.
De Bock L, Boussery K, Colin P, De Smet J, T’Jollyn H, Van Bocxlaer J: Development and validation of a fast and sensitive UPLC-MS/MS method for the quantification of six probe metabolites for the in vitro determination of cytochrome P450 activity. Talanta 2012; 89: 209–216.
20.
Kozakai K, Yamada Y, Oshikata M, Kawase T, Suzuki E, Haramaki Y, Taniguchi H: Reliable high-throughput method for inhibition assay of 8 cytochrome P450 isoforms using cocktail of probe substrates and stable isotope-labeled internal standards. Drug Metab Pharmacokinet 2012; 27:520–529.
21.
Christensen CM, Morris RS, Kapsandoy SC, Archer M, Kuang J, Shane-McWhorter L, Bray BE, Zeng-Treitler Q: Patient needs and preferences for herb-drug-disease interaction alerts: a structured interview study. BMC Complement Altern Med 2017; 17: 272.
22.
Hao DC, Xiao PG: Impact of drug metabolism-pharmacokinetics and their relevance upon salvia-based drug discovery. Curr Drug Metab 2017, Epub ahead of print.
23.
Zhang XL, Chen M, Zhu LL, Zhou Q: Therapeutic risk and benefits of concomitantly using herbal medicines and conventional medicines: from the perspectives of evidence based on randomized controlled trials and clinical risk management. Evid Based Complement Alternat Med 2017; 2017: 9296404.
24.
Li CY, Wang EQ, Cheng Y, Bao JK: Oridonin: an active diterpenoid targeting cell cycle arrest, apoptotic and autophagic pathways for cancer therapeutics. Int J Biochem Cell Biol 2011; 43: 701–704.
25.
Liu Y, Shi QF, Qi M, Tashiro S, Onodera S, Ikejima T: Interruption of hepatocyte growth factor signaling augmented oridonin-induced death in human non-small cell lung cancer A549 cells via c-met-nuclear factor-κB-cyclooxygenase-2 and c-met-Bcl-2-caspase-3 pathways. Biol Pharm Bull 2012; 35: 1150–1158.
26.
Zhang T, Tan Y, Zhao R, Liu Z: DNA damage induced by oridonin involves cell cycle arrest at G2/M phase in human MCF-7 cells. Contemp Oncol (Pozn) 2013; 17: 38–44.
27.
Li AP, Kaminski DL, Rasmussen A: Substrates of human hepatic cytochrome P450 3A4. Toxicology 1995; 104: 1–8.
28.
Purkins L, Wood N, Ghahramani P, Love ER, Eve MD, Fielding A: Coadministration of voriconazole and phenytoin: pharmacokinetic interaction, safety, and toleration. Br J Clin Pharmacol 2003; 56(suppl 1):37–44.
29.
Lim ML, Min SS, Eron JJ, Bertz RJ, Robinson M, Gaedigk A, Kashuba A: Coadministration of lopinavir/ritonavir and phenytoin results in two-way drug interaction through cytochrome P-450 induction. J Acquir Immune Defic Syndr 2004; 36: 1034–1040.
30.
Wypasek E, Ciesla M, Suder B, Janik L, Sadowski J, Undas A: CYP2C9 polymorphism and unstable anticoagulation with warfarin in patients within the first 3 months following heart valve replacement. Adv Clin Exp Med 2015; 24: 607–614.
31.
Schuetz E, Lan L, Yasuda K, Kim R, Kocarek TA, Schuetz J, Strom S: Development of a real-time in vivo transcription assay: application reveals pregnane X receptor-mediated induction of CYP3A4 by cancer chemotherapeutic agents. Mol Pharmacol 2002; 62: 439–445.
32.
Colburn DE, Giles FJ, Oladovich D, Smith JA: In vitro evaluation of cytochrome P450-mediated drug interactions between cytarabine, idarubicin, itraconazole and caspofungin. Hematology 2004; 9: 217–221.
33.
Kamdem LK, Flockhart DA, Desta Z: In vitro cytochrome P450-mediated metabolism of exemestane. Drug Metab Dispos 2011; 39: 98–105.
34.
Zhao C, Han SY, Li PP: Pharmacokinetics of Gefitinib: Roles of drug metabolizing enzymes and transporters. Curr Drug Deliv 2017; 14:282–288.
35.
Choudhary C, Kumar C, Gnad F, Nielsen ML, Rehman M, Walther TC, Olsen JV, Mann M: Lysine acetylation targets protein complexes and co-regulates major cellular functions. Science 2009; 325: 834–840.
36.
Wang Y, Guan S, Acharya P, Koop DR, Liu Y, Liao M, Burlingame AL, Correia MA: Ubiquitin-dependent proteasomal degradation of human liver cytochrome P450 2E1: identification of sites targeted for phosphorylation and ubiquitination. J Biol Chem 2011; 286: 9443–9456.
© 2018 S. Karger AG, Basel
2018
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.