Planta Med 2020; 86(12): 867-875
DOI: 10.1055/a-1178-0852
Biological and Pharmacological Activity
Original Papers

Differential Effects of Components in Artemisia annua Extract on the Induction of Drug-Metabolizing Enzyme Expression Mediated by Nuclear Receptors

Xueli Zhang
School of Pharmaceutical Sciences, Shandong University, Jinan, R. P. China
,
Ran Meng
School of Pharmaceutical Sciences, Shandong University, Jinan, R. P. China
,
Haina Wang
School of Pharmaceutical Sciences, Shandong University, Jinan, R. P. China
,
Jie Xing
School of Pharmaceutical Sciences, Shandong University, Jinan, R. P. China
› Author Affiliations
Supported by: Natural Science Foundation of Shandong Province No. ZR2017MH030

Abstract

Artemisia annua tea is a popular dosage form used to treat and prevent malaria in some developing countries. However, repeated drinking leads to an obviously decreased efficacy, which may be related to the induction of metabolizing enzymes by artemisinin. In the present study, the ability of different components in A. annua to activate the pregnane X receptor and constitutive androstane receptor was evaluated by the dual luciferase reporter gene system. The changes in mRNA and protein expression of CYP3A4 and CYP2B6 were determined by quantitative real-time PCR and Western blotting. Results showed that in the pregnane X receptor-mediated CYP3A4 reporter gene system, chrysosplenetin and arteannuin B exhibited a weak induction effect on pregnane X receptor wt, while arteannuin A had a strong induction effect on pregnane X receptor wt and pregnane X receptor 370 and a weak induction effect on pregnane X receptor 163. In the pregnane X receptor-mediated CYP2B6 reporter gene system, arteannuin A had a moderate induction effect on pregnane X receptor wt and pregnane X receptor 379, and a weak induction effect on pregnane X receptor 403, while arteannuin B had a weak induction effect on pregnane X receptor wt and pregnane X receptor 379. Arteannuin A had a strong induction effect on constitutive androstane receptor 3 in constitutive androstane receptor-mediated CYP3A4/2B6 reporter gene systems, while arteannuin B showed a weak induction effect on constitutive androstane receptor 3 in the constitutive androstane receptor-mediated CYP2B6 reporter gene system. The mRNA and protein expressions of CYP3A4 and CYP2B6 were increased when the pregnane X receptor or constitutive androstane receptor was activated. Various components present in A. annua differentially affect the activities of pregnane X receptor isoforms and the constitutive androstane receptor, which indicates the possibility of a drug-drug interaction. This partly explains the decline in efficacy after repeated drinking of A. annua tea.



Publication History

Received: 30 October 2019

Accepted: 05 May 2020

Article published online:
17 June 2020

Georg Thieme Verlag KG
Stuttgart · New York

 
  • References

  • 1 Cowman AF, Healer J, Marapana D, Marsh K. Malaria: biology and disease. Cell 2016; 167: 610-624
  • 2 White NJ, Pukrittayakamee S, Hien TT, Faiz MA, Mokuolu OA, Dondorp AM. Malaria. Lancet 2014; 383: 723-735
  • 3 WHO. World malaria report 2018. Available at (Accessed January 4, 2019): https://www.who.int/malaria/publications/world-malaria-report-2018/en/
  • 4 Krungkrai J, Krungkrai SR. Antimalarial qinghaosu/artemisinin: The therapy worthy of a Nobel Prize. Asian Pac J Trop Biomed 2016; 6: 371-375
  • 5 Li Y. Qinghaosu (artemisinin): chemistry and pharmacology. Acta Pharmacol Sin 2012; 33: 1141-1146
  • 6 WHO. Guidelines for the treatment of malaria Third edition. Available at (Accessed February 26, 2019): https://extranetwhoint/rhl/guidelines/guidelines-treatment-malaria-third-edition
  • 7 OʼConnell KA, Gatakaa H, Poyer S, Njogu J, Evance I, Munroe E, Solomon T, Goodman C, Hanson K, Zinsou C, Akulayi L, Raharinjatovo J, Arogundade E, Buyungo P, Mpasela F, Adjibabi CB, Agbango JA, Ramarosandratana BF, Coker B, Rubahika D, Hamainza B, Chapman S, Shewchuk T, Chavasse D. Got ACTs? Availability, price, market share and provider knowledge of anti-malarial medicines in public and private sector outlets in six malaria-endemic countries. Malar J 2011; 10: 326
  • 8 Ferreira JFS, Benedito VA, Sandhu D, Marchese JA, Liu S. Seasonal and differential sesquiterpene accumulation in Artemisia annua suggest selection based on both artemisinin and dihydroartemisinic acid may increase artemisinin in planta . Front Plant Sci 2018; 9: 1096
  • 9 de Ridder S, van der Kooy F, Verpoorte R. Artemisia annua as a self-reliant treatment for malaria in developing countries. J Ethnopharmacol 2008; 120: 302-314
  • 10 Willcox M. Artemisia species: from traditional medicines to modern antimalarials – and back again. J Altern Complement Med 2009; 15: 101-109
  • 11 Liu CX. Discovery and development of artemisinin and related compounds. Chin Herb Med 2017; 9: 101-114
  • 12 van der Kooy F, Sullivan SE. The complexity of medicinal plants: the traditional Artemisia annua formulation, current status and future perspectives. J Ethnopharmacol 2013; 150: 1-13
  • 13 Suberu JO, Gorka AP, Jacobs L, Roepe PD, Sullivan N, Barker GC, Lapkin AA. Anti-plasmodial polyvalent interactions in Artemisia annua L. aqueous extract – possible synergistic and resistance mechanisms. PLoS One 2013; 8: e80790
  • 14 Ferreira JF, Luthria DL, Sasaki T, Heyerick A. Flavonoids from Artemisia annua L. as antioxidants and their potential synergism with artemisinin against malaria and cancer. Molecules 2010; 15: 3135-3170
  • 15 Rasoanaivo P, Wright CW, Willcox ML, Gilbert B. Whole plant extracts versus single compounds for the treatment of malaria: synergy and positive interactions. Malar J 2011; 10 (Suppl. 01) S4
  • 16 Mouton J, Jansen O, Frederich M, van der Kooy F. Is artemisinin the only antiplasmodial compound in the Artemisia annua tea infusion? An in vitro study. Planta Med 2013; 79: 468-470
  • 17 Blanke CH, Naisabha GB, Balema MB, Mbaruku GM, Heide L, Muller MS. Herba Artemisiae annuae tea preparation compared to sulfadoxine-pyrimethamine in the treatment of uncomplicated falciparum malaria in adults: a randomized double-blind clinical trial. Trop Doct 2008; 38: 113-116
  • 18 Wanwimolruk S, Phopin K, Prachayasittikul V. Cytochrome P450 enzyme mediated herbal drug interactions (Part 2). EXCLI J 2014; 13: 869-896
  • 19 Wanwimolruk S, Prachayasittikul V. Cytochrome P450 enzyme mediated herbal drug interactions (Part 1). EXCLI J 2014; 13: 347-391
  • 20 Tirona RG, Bailey DG. Herbal product-drug interactions mediated by induction. Br J Clin Pharmacol 2006; 61: 677-681
  • 21 Durr D, Stieger B, Kullak-Ublick GA, Rentsch KM, Steinert HC, Meier PJ, Fattinger K. St Johnʼs Wort induces intestinal P-glycoprotein/MDR1 and intestinal and hepatic CYP3A4. Clin Pharmacol Ther 2000; 68: 598-604
  • 22 Leucuta SE, Vlase L. Pharmacokinetics and metabolic drug interactions. Curr Clin Pharmacol 2006; 1: 5-20
  • 23 Svensson USH, Ashton M. Identification of the human cytochrome P450 enzymes involved in the in vitro metabolism of artemisinin. Brit J Clin Pharmaco 1999; 48: 528-535
  • 24 Gao J, Xie W. Targeting xenobiotic receptors PXR and CAR for metabolic diseases. Trends Pharmacol Sci 2012; 33: 552-558
  • 25 Faucette SR, Sueyoshi T, Smith CM, Negishi M, Lecluyse EL, Wang H. Differential regulation of hepatic CYP2B6 and CYP3A4 genes by constitutive androstane receptor but not pregnane X receptor. J Pharmacol Exp Ther 2006; 317: 1200-1209
  • 26 Wang X, Bai KH, Sun K, Zhang SQ. Inductive effects of artemisinin-based antimalarials on nuclear receptor CAR and CYP2B in rats liver. Chin Rem Clin 2010; 10: 849-851
  • 27 Burk O, Arnold KA, Nussler AK, Schaeffeler E, Efimova E, Avery BA, Avery MA, Fromm MF, Eichelbaum M. Antimalarial artemisinin drugs induce cytochrome P450 and MDR1 expression by activation of xenosensors pregnane X receptor and constitutive androstane receptor. Mol Pharmacol 2005; 67: 1954-1965
  • 28 Zang M, Zhao L, Zhu F, Li X, Yang A, Xing J. Effect of CAR polymorphism on the pharmacokinetics of artemisinin in healthy Chinese subjects. Drug Metab Pharmacokinet 2015; 30: 123-126
  • 29 Agrawal V, Choi JH, Giacomini KM, Miller WL. Substrate-specific modulation of CYP3A4 activity by genetic variants of cytochrome P450 oxidoreductase. Pharmacogenet Genomics 2010; 20: 611-618
  • 30 Brewer CT, Chen T. PXR variants: the impact on drug metabolism and therapeutic responses. Acta Pharm Sin B 2016; 6: 441-449
  • 31 Luo G, Cunningham M, Kim S, Burn T, Lin J, Sinz M, Hamilton G, Rizzo C, Jolley S, Gilbert D, Downey A, Mudra D, Graham R, Carroll K, Xie J, Madan A, Parkinson A, Christ D, Selling B, LeCluyse E, Gan LS. CYP3A4 induction by drugs: correlation between a pregnane X receptor reporter gene assay and CYP3A4 expression in human hepatocytes. Drug Metab Dispos 2002; 30: 795-804
  • 32 Cai TY, Zhang YR, Ji JB, Xing J. Investigation of the component in Artemisia annua L. leading to enhanced antiplasmodial potency of artemisinin via regulation of its metabolism. J Ethnopharmacol 2017; 207: 86-91
  • 33 Pal D, Mitra AK. MDR- and CYP3A4-mediated drug-drug interactions. J Neuroimmune Pharmacol 2006; 1: 323-339
  • 34 Lemaire G, de Sousa G, Rahmani R. A PXR reporter gene assay in a stable cell culture system: CYP3A4 and CYP2B6 induction by pesticides. Biochem Pharmacol 2004; 68: 2347-2358
  • 35 Na DH, Ji HY, Park EJ, Kim MS, Liu KH, Lee HS. Evaluation of metabolism-mediated herb-drug interactions. Arch Pharm Res 2011; 34: 1829-1842
  • 36 Auerbach SS, Stoner MA, Su S, Omiecinski CJ. Retinoid X receptor-alpha-dependent transactivation by a naturally occurring structural variant of human constitutive androstane receptor (NR1I3). Mol Pharmacol 2005; 68: 1239-1253
  • 37 Pinne M, Ponce E, Raucy JL. Transactivation assays to assess canine and Rodent Pregnane X Receptor (PXR) and Constitutive Androstane Receptor (CAR) Activation. PLoS One 2016; 11: e0164642
  • 38 Tanaka E. Clinically important pharmacokinetic drug-drug interactions: role of cytochrome P450 enzymes. J Clin Pharm Ther 1998; 23: 403-416
  • 39 Prakash C, Zuniga B, Song CS, Jiang S, Cropper J, Park S, Chatterjee B. Nuclear receptors in drug metabolism, drug response and drug interactions. Nucl Receptor Res 2015; 2: 101178
  • 40 Lamba JK, Lin YS, Schuetz EG, Thummel KE. Genetic contribution to variable human CYP3A-mediated metabolism. Adv Drug Deliv Rev 2012; 64: 256-269
  • 41 Lim YP, Liu CH, Shyu LJ, Huang JD. Functional characterization of a novel polymorphism of pregnane X receptor, Q158K, in Chinese subjects. Pharmacogenet Genomics 2005; 15: 337-341
  • 42 Hustert E, Zibat A, Presecan-Siedel E, Eiselt R, Mueller R, Fuss C, Brehm I, Brinkmann U, Eichelbaum M, Wojnowski L, Burk O. Natural protein variants of pregnane X receptor with altered transactivation activity toward CYP3A4. Drug Metab Dispos 2001; 29: 1454-1459
  • 43 Lamba J, Lamba V, Schuetz E. Genetic variants of PXR (NR1I2) and CAR (NR1I3) and their implications in drug metabolism and pharmacogenetics. Curr Drug Metab 2005; 6: 369-383
  • 44 Bosch TM, Deenen M, Pruntel R, Smits PH, Schellens JH, Beijnen JH, Meijerman I. Screening for polymorphisms in the PXR gene in a Dutch population. Eur J Clin Pharmacol 2006; 62: 395-399
  • 45 Koyano S, Kurose K, Saito Y, Ozawa S, Hasegawa R, Komamura K, Ueno K, Kamakura S, Kitakaze M, Nakajima T, Matsumoto K, Akasawa A, Saito H, Sawada J. Functional characterization of four naturally occurring variants of human pregnane X receptor (PXR): one variant causes dramatic loss of both DNA binding activity and the transactivation of the CYP3A4 promoter/enhancer region. Drug Metab Dispos 2004; 32: 149-154
  • 46 Oladimeji PO, Chen T. PXR: more than just a master xenobiotic receptor. Mol Pharmacol 2018; 93: 119-127
  • 47 Lim YP, Huang JD. Pregnane X receptor polymorphism affects CYP3A4 induction via a ligand-dependent interaction with steroid receptor coactivator-1. Pharmacogenet Genomics 2007; 17: 369-382
  • 48 Rana M, Devi S, Gourinath S, Goswami R, Tyagi RK. A comprehensive analysis and functional characterization of naturally occurring non-synonymous variants of nuclear receptor PXR. Biochim Biophys Acta 2016; 1859: 1183-1197