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DOI: 10.1055/s-0042-103689
Modulation of CYPs, P-gp, and PXR by Eschscholzia californica (California Poppy) and Its Alkaloids
Publication History
received 09 January 2016
revised 10 February 2016
accepted 13 February 2016
Publication Date:
07 April 2016 (online)
![](https://www.thieme-connect.de/media/plantamedica/201606/lookinside/thumbnails/10-1055-s-0042-103689_pma0023-1.jpg)
Abstract
Eschscholzia californica, a native US plant, is traditionally used as a sedative, analgesic, and anxiolytic herb. With the rapid rise in the use of herbal supplements together with over-the-counter and prescription drugs, the risk for potential herb-drug interactions is also increasing. Most of the clinically relevant pharmacokinetic drug interactions occur due to modulation of cytochrome P450 enzymes (CYPs), P-glycoprotein, and the pregnane X receptor by concomitantly used herbs. This study aimed to determine the effects of an EtOH extract, aqueous extract (tea), basic CHCl3 fractions, and isolated major alkaloids, namely protopine (1), escholtzine (2), allocryptopine (3), and californidine (4), of E. californica on the activity of cytochrome P450s, P-glycoprotein and the pregnane X receptor. The EtOH extract and fractions showed strong time-dependent inhibition of CYP 3A4, CYP 2C9, and CYP 2C19, and reversible inhibition of CYP 2D6. Among the alkaloids, escholtzine (2) and allocryptopine (3) exhibited time-dependent inhibition of CYP 3A4, CYP 2C9, and CYP 2C19 (IC50 shift ratio > 2), while protopine (1) and allocryptopine (3) showed reversible inhibition of CYP 2D6 enzyme. A significant activation of the pregnane X receptor (> 2-fold) was observed with the EtOH extract, basic CHCl3 fraction, and alkaloids (except protopine), which resulted into an increased expression of mRNA and the activity of CYP 3A4 and CYP 1A2. The expression of P-glycoprotein was unaffected. However, aqueous extract (tea) and its main alkaloid californidine (4) did not affect cytochrome P450s, P-glycoprotein, or the pregnane X receptor. This data suggests that EtOH extract of E. californica and its major alkaloids have a potential of causing interactions with drugs that are metabolized by cytochrome P450s, while the tea seems to be safer.
Key words
Eschscholzia californica - Papaveraceae - alkaloids - herb-drug interactions - CYPs - P-gp - PXR-
References
- 1 Rolland A, Fleurentin J, Lanhers MC, Younos C, Misslin R, Mortier F, Pelt JM. Behavioural effects of the American traditional plant Eschscholzia californica: sedative and anxiolytic properties. Planta Med 1991; 57: 212-216
- 2 Schafer HL, Schafer H, Schneider W, Elstner EF. Sedative action of extract combinations of Eschscholtzia californica and Corydalis cava . Arzneimittelforschung 1995; 45: 124-126
- 3 Oga EF, Sekine S, Shitara Y, Horie T. Pharmacokinetic herb-drug interactions: insight into mechanisms and consequences. Eur J Drug Metab Pharmacokinet advance online publication 28.08.2015; DOI: 10.1007/s13318-015-0296-z.
- 4 Zhang L, Zhang YD, Zhao P, Huang SM. Predicting drug-drug interactions: an FDA perspective. AAPS J 2009; 11: 300-306
- 5 Sprouse AA, van Breemen RB. Pharmacokinetic Interactions between Drugs and Botanical Dietary Supplements. Drug Metab Dispos 2016; 44: 162-171
- 6 Gafner S, Dietz BM, McPhail KL, Scott IM, Glinski JA, Russell FE, McCollom MM, Budzinski JW, Foster BC, Bergeron C, Rhyu MR, Bolton JL. Alkaloids from Eschscholzia californica and their capacity to inhibit binding of [3H]8-Hydroxy-2-(di-N-propylamino)tetralin to 5-HT1A receptors in vitro . J Nat Prod 2006; 69: 432-435
- 7 Paul LD, Springer D, Staack RF, Kraemer T, Maurer HH. Cytochrome P450 isoenzymes involved in rat liver microsomal metabolism of californine and protopine. Eur J Pharmacol 2004; 485: 69-79
- 8 Takahashi H, Iguchi M, Onda M. Utilization of Protopine and Related Alkaloids. XVII. Spectroscopic Studies on the Ten-Membered Ring Conformations of Protopine and α-Allocryptopine. Chem Pharm Bull 1985; 33: 4775-4782
- 9 Meng Q, Liu K. Pharmacokinetic interactions between herbal medicines and prescribed drugs: focus on drug metabolic enzymes and transporters. Curr Drug Metab 2014; 15: 791-807
- 10 Li J, Godecke T, Chen SN, Imai A, Lankin DC, Farnsworth NR, Pauli GF, van Breemen RB, Nikolic D. In vitro metabolic interactions between black cohosh (Cimicifuga racemosa) and tamoxifen via inhibition of cytochromes P450 2D6 and 3A4. Xenobiotica advance online publication 09.08.2011; DOI: 10.3109/00498254.2011.603385.
- 11 Jung ST, Lauchli R, Arnold FH. Cytochrome P450: taming a wild type enzyme. Curr Opin Biotechnol 2011; 22: 809-817
- 12 Kamel A, Harriman S. Inhibition of cytochrome P450 enzymes and biochemical aspects of mechanism-based inactivation (MBI). Drug Discov Today Technol 2013; 10: e177-e189
- 13 Riley RJ, Wilson CE. Cytochrome P450 time-dependent inhibition and induction: advances in assays, risk analysis and modelling. Expert Opin Drug Metab Toxicol 2015; 11: 557-572
- 14 Salminen KA, Meyer A, Imming P, Raunio H. CYP2C19 progress curve analysis and mechanism-based inactivation by three methylenedioxyphenyl compounds. Drug Metab Dispos 2011; 39: 2283-2289
- 15 Iwata H, Tezuka Y, Kadota S, Hiratsuka A, Watabe T. Identification and characterization of potent CYP3A4 inhibitors in Schisandra fruit extract. Drug Metab Dispos 2004; 32: 1351-1358
- 16 Wang YM, Ong SS, Chai SC, Chen T. Role of CAR and PXR in xenobiotic sensing and metabolism. Expert Opin Drug Metab Toxicol 2012; 8: 803-817
- 17 Jain S, Rathod V, Prajapati R, Nandekar PP, Sangamwar AT. Pregnane X Receptor and P-glycoprotein: a connexion for Alzheimerʼs disease management. Mol Divers 2014; 18: 895-909
- 18 Tao Y, Xu H, Wang S, Wang B, Zhang Y, Wang W, Huang B, Wu H, Li D, Zhang Y, Xiao X, Li Y, Yang H, Huang L. Identification of the absorbed constituents after oral administration of Yuanhu Zhitong prescription extract and its pharmacokinetic study by rapid resolution liquid chromatography/quadrupole time-of-flight. J Chromatogr B Analyt Technol Biomed Life Sci 2013; 935: 1-9
- 19 Ilias M, Samoylenko V, Gillum VD. Preparation of pre-coated rp-rotors and universal chromatorotors, chromatographic separation devices and methods for centrifugal preparative chromatography. WO Patent WO 2013036803 A8, 2013
- 20 Crespi CL, Miller VP, Penman BW. Microtiter plate assays for inhibition of human, drug-metabolizing cytochromes P450. Anal Biochem 1997; 248: 188-190
- 21 Manda VK, Avula B, Ali Z, Wong YH, Smillie TJ, Khan IA, Khan SI. Characterization of in vitro ADME properties of diosgenin and dioscin from Dioscorea villosa . Planta Med 2013; 79: 1421-1428
- 22 Manda VK, Avula B, Dale OR, Chittiboyina AG, Khan IA, Walker LA, Khan SI. Studies on Pharmacokinetic Drug Interaction Potential of Vinpocetine. Medicines 2015; 2: 93-105
- 23 Obach RS, Walsky RL, Venkatakrishnan K. Mechanism-based inactivation of human cytochrome p450 enzymes and the prediction of drug-drug interactions. Drug Metab Dispos 2007; 35: 246-255
- 24 Manda VK, Avula B, Chittiboyina AG, Khan IA, Walker LA, Khan SI. Inhibition of CYP3A4 and CYP1A2 by Aegle marmelos and its constituents. Xenobiotica 2016; 46: 117-125
- 25 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
- 26 Goodwin B, Hodgson E, Liddle C. The orphan human pregnane X receptor mediates the transcriptional activation of CYP3A4 by rifampicin through a distal enhancer module. Mol Pharmacol 1999; 56: 1329-1339
- 27 Rautio J, Humphreys JE, Webster LO, Balakrishnan A, Keogh JP, Kunta JR, Serabjit-Singh CJ, Polli JW. In vitro p-glycoprotein inhibition assays for assessment of clinical drug interaction potential of new drug candidates: a recommendation for probe substrates. Drug Metab Dispos 2006; 34: 786-792
- 28 Liu XL, Tee HW, Go ML. Functionalized chalcones as selective inhibitors of P-glycoprotein and breast cancer resistance protein. Bioorg Med Chem 2008; 16: 171-180
- 29 Manda VK, Avula B, Ali Z, Khan IA, Walker LA, Khan SI. Evaluation of in vitro absorption, distribution, metabolism, and excretion (ADME) properties of mitragynine, 7-hydroxymitragynine, and mitraphylline. Planta Med 2014; 80: 568-576