Download PDF
Planta Med 2022; 88(02): 152-162
DOI: 10.1055/a-1305-3936
Biological and Pharmacological Activity
Original Papers

Constituents of Passiflora incarnata, but Not of Valeriana officinalis, Interact with the Organic Anion Transporting Polypeptides (OATP)2B1 and OATP1A2

Anima M. Schäfer 
1   Biopharmacy, Department Pharmaceutical Sciences, University of Basel, Basel, Switzerland
,
Pierrine M. Gilgen
1   Biopharmacy, Department Pharmaceutical Sciences, University of Basel, Basel, Switzerland
,
Clara Spirgi
1   Biopharmacy, Department Pharmaceutical Sciences, University of Basel, Basel, Switzerland
,
Olivier Potterat 
2   Pharmaceutical Biology, Department Pharmaceutical Sciences, University of Basel, Basel, Switzerland
,
Henriette E. Meyer zu Schwabedissen
1   Biopharmacy, Department Pharmaceutical Sciences, University of Basel, Basel, Switzerland
› Author Affiliations
› Further Information
    Permissions and Reprints

Abstract

Herbal medication used in the treatment of sleep disorders and anxiety often contain extracts of Valeriana officinalis or Passiflora incarnata. Valerenic acid in V. officinalis and apigenin, orientin, and vitexin in P. incarnata are thought to contribute to their therapeutic effect. It was the aim of this study to test whether these constituents of herbal extracts are interacting with the uptake of estrone 3-sulfate, pregnenolone sulfate, and dehydroepiandrosterone sulfate mediated by the uptake transporters organic anion transporting polypeptide 2B1 (OATP2B1) or organic anion transporting polypeptide 1A2 (OATP1A2). Madin-Darby canine kidney cells overexpressing OATP2B1 or OATP1A2 were used to determine the influence of the constituents on the cellular accumulation of the sulfated steroids. Subsequently, competitive counterflow experiments were applied to test whether identified inhibitors are also substrates of the transporters. Valerenic acid only interacted with OATP2B1, whereas apigenin, orientin, and vitexin interacted with OATP2B1 and OATP1A2. Competitive counterflow revealed that orientin is a substrate of both transporters, while apigenin was transported by OATP1A2 and vitexin by OATP2B1. In a next step, commercially available P. incarnata preparations were assessed for their influence on the transporters, revealing inhibition of transporter-mediated estrone 3-sulfate uptake. HPLC-UV-MS analysis confirmed the presence of orientin and vitexin in these preparations, thereby suggesting that these constituents are involved in the interaction. Our data indicate that constituents of P. incarnata may alter the function of OATP2B1 and OATP1A2, which could affect the uptake of other compounds relying on uptake mediated by the transporters.

Key words

OATP2B1 - OATP1A2 - interaction - sulfated steroids - Passiflora incarnata - Passifloraceae - Valeriana officinalis - Caprifoliaceae

Supporting Information

    HPLC-MS chromatographic traces of commercial formulations and reference substances are available as Supporting Information.

  • Supporting Information


Publication History

Received: 08 July 2020

Accepted after revision: 06 November 2020

Article published online:
28 January 2021

© 2021. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • References

  • 1 Kobayashi D, Nozawa T, Imai K, Nezu J, Tsuji A, Tamai I. Involvement of human organic anion transporting polypeptide OATP-B (SLC21A9) in pH-dependent transport across intestinal apical membrane. J Pharmacol Exp Ther 2003; 306: 703-708
    CrossrefPubMedGoogle Scholar
  • 2 Kullak-Ublick GA, Ismair MG, Stieger B, Landmann L, Huber R, Pizzagalli F, Fattinger K, Meier PJ, Hagenbuch B. Organic anion-transporting polypeptide B (OATP-B) and its functional comparison with three other OATPs of human liver. Gastroenterology 2001; 120: 525-533
    CrossrefPubMedGoogle Scholar
  • 3 Ferreira C, Hagen P, Stern M, Hussner J, Zimmermann U, Grube M, Meyer zu Schwabedissen HE. The scaffold protein PDZK1 modulates expression and function of the organic anion transporting polypeptide 2B1. Eur J Pharm Sci 2018; 120: 181-190
    CrossrefPubMedGoogle Scholar
  • 4 Pizzagalli F, Varga Z, Huber RD, Folkers G, Meier PJ, St-Pierre MV. Identification of steroid sulfate transport processes in the human mammary gland. J Clin Endocrinol Metab 2003; 88: 3902-3912
    CrossrefPubMedGoogle Scholar
  • 5 Meyer zu Schwabedissen HE, Ferreira C, Schaefer AM, Oufir M, Seibert I, Hamburger M, Tirona RG. Thyroid hormones are transport substrates and transcriptional regulators of organic anion transporting polypeptide 2B1. Mol Pharmacol 2018; 94: 700-712
    CrossrefPubMedGoogle Scholar
  • 6 Grube M, Kock K, Oswald S, Draber K, Meissner K, Eckel L, Bohm M, Felix SB, Vogelgesang S, Jedlitschky G, Siegmund W, Warzok R, Kroemer HK. Organic anion transporting polypeptide 2B1 is a high-affinity transporter for atorvastatin and is expressed in the human heart. Clin Pharmacol Ther 2006; 80: 607-620
    CrossrefPubMedGoogle Scholar
  • 7 Schaefer AM, Bock T, Meyer zu Schwabedissen HE. Establishment and validation of competitive counterflow as a method to detect substrates of the organic anion transporting polypeptide 2B1. Mol Pharm 2018; 15: 5501-5513
    CrossrefPubMedGoogle Scholar
  • 8 Shirasaka Y, Mori T, Murata Y, Nakanishi T, Tamai I. Substrate- and dose-dependent drug interactions with grapefruit juice caused by multiple binding sites on OATP2B1. Pharm Res 2014; 31: 2035-2043
    CrossrefPubMedGoogle Scholar
  • 9 Satoh H, Yamashita F, Tsujimoto M, Murakami H, Koyabu N, Ohtani H, Sawada Y. Citrus juices inhibit the function of human organic anion-transporting polypeptide OATP-B. Drug Metab Dispos 2005; 33: 518-523
    CrossrefPubMedGoogle Scholar
  • 10 Grube M, Reuther S, Meyer zu Schwabedissen H, Kock K, Draber K, Ritter CA, Fusch C, Jedlitschky G, Kroemer HK. Organic anion transporting polypeptide 2B1 and breast cancer resistance protein interact in the transepithelial transport of steroid sulfates in human placenta. Drug Metab Dispos 2007; 35: 30-35
    CrossrefPubMedGoogle Scholar
  • 11 Gao B, Vavricka SR, Meier PJ, Stieger B. Differential cellular expression of organic anion transporting peptides OATP1A2 and OATP2B1 in the human retina and brain: implications for carrier-mediated transport of neuropeptides and neurosteriods in the CNS. Pflugers Arch 2015; 467: 1481-1493
    CrossrefPubMedGoogle Scholar
  • 12 Loubiere LS, Vasilopoulou E, Bulmer JN, Taylor PM, Stieger B, Verrey F, McCabe CJ, Franklyn JA, Kilby MD, Chan SY. Expression of thyroid hormone transporters in the human placenta and changes associated with intrauterine growth restriction. Placenta 2010; 31: 295-304
    CrossrefPubMedGoogle Scholar
  • 13 Lee W, Glaeser H, Smith LH, Roberts RL, Moeckel GW, Gervasini G, Leake BF, Kim RB. Polymorphisms in human organic anion-transporting polypeptide 1A2 (OATP1A2): implications for altered drug disposition and central nervous system drug entry. J Biol Chem 2005; 280: 9610-9617
    CrossrefPubMedGoogle Scholar
  • 14 Schäfer AM, Meyer zu Schwabedissen HE, Bien-Moller S, Hubeny A, Vogelgesang S, Oswald S, Grube M. OATP1A2 and OATP2B1 are interacting with dopamine-receptor agonists and antagonists. Mol Pharm 2020; 17: 1987-1995
    CrossrefPubMedGoogle Scholar
  • 15 Gao B, Hagenbuch B, Kullak-Ublick GA, Benke D, Aguzzi A, Meier PJ. Organic anion-transporting polypeptides mediate transport of opioid peptides across blood-brain barrier. J Pharmacol Exp Ther 2000; 294: 73-79
    PubMedGoogle Scholar
  • 16 Ho RH, Tirona RG, Leake BF, Glaeser H, Lee W, Lemke CJ, Wang Y, Kim RB. Drug and bile acid transporters in rosuvastatin hepatic uptake: function, expression, and pharmacogenetics. Gastroenterology 2006; 130: 1793-1806
    CrossrefPubMedGoogle Scholar
  • 17 Grube M, Hagen P, Jedlitschky G. Neurosteroid transport in the brain: Role of ABC and SLC transporters. Front Pharmacol 2018; 9: 354
    CrossrefPubMedGoogle Scholar
  • 18 Meyer zu Schwabedissen HE, Tirona RG, Yip CS, Ho RH, Kim RB. Interplay between the nuclear receptor pregnane X receptor and the uptake transporter organic anion transporter polypeptide 1A2 selectively enhances estrogen effects in breast cancer. Cancer Res 2008; 68: 9338-9347
    CrossrefPubMedGoogle Scholar
  • 19 Johnson EJ, Won CS, Kock K, Paine MF. Prioritizing pharmacokinetic drug interaction precipitants in natural products: application to OATP inhibitors in grapefruit juice. Biopharm Drug Dispos 2017; 38: 251-259
    CrossrefPubMedGoogle Scholar
  • 20 Bailey DG, Dresser GK, Leake BF, Kim RB. Naringin is a major and selective clinical inhibitor of organic anion-transporting polypeptide 1A2 (OATP1A2) in grapefruit juice. Clin Pharmacol Ther 2007; 81: 495-502
    CrossrefPubMedGoogle Scholar
  • 21 Navratilova L, Ramos Mandikova J, Pavek P, Mladenka P, Trejtnar F. Honey flavonoids inhibit hOATP2B1 and hOATP1A2 transporters and hOATP-mediated rosuvastatin cell uptake in vitro . Xenobiotica 2018; 48: 745-755
    CrossrefPubMedGoogle Scholar
  • 22 Roth M, Timmermann BN, Hagenbuch B. Interactions of green tea catechins with organic anion-transporting polypeptides. Drug Metab Dispos 2011; 39: 920-926
    CrossrefPubMedGoogle Scholar
  • 23 Schäfer AM, Potterat O, Seibert I, Fertig O, Meyer zu Schwabedissen HE. Hyperforin-induced activation of the pregnane X receptor is influenced by the organic anion-transporting polypeptide 2B1. Mol Pharmacol 2019; 95: 313-323
    CrossrefPubMedGoogle Scholar
  • 24 Akhondzadeh S, Naghavi HR, Vazirian M, Shayeganpour A, Rashidi H, Khani M. Passionflower in the treatment of generalized anxiety: a pilot double-blind randomized controlled trial with oxazepam. J Clin Pharm Ther 2001; 26: 363-367
    CrossrefPubMedGoogle Scholar
  • 25 Lolli LF, Sato CM, Romanini CV, Villas-Boas Lde B, Santos CA, de Oliveira RM. Possible involvement of GABA A-benzodiazepine receptor in the anxiolytic-like effect induced by Passiflora actinia extracts in mice. J Ethnopharmacol 2007; 111: 308-314
    CrossrefPubMedGoogle Scholar
  • 26 Grundmann O, Wang J, McGregor GP, Butterweck V. Anxiolytic activity of a phytochemically characterized Passiflora incarnata extract is mediated via the GABAergic system. Planta Med 2008; 74: 1769-1773
    Article in Thieme ConnectPubMedGoogle Scholar
  • 27 Appel K, Rose T, Fiebich B, Kammler T, Hoffmann C, Weiss G. Modulation of the gamma-aminobutyric acid (GABA) system by Passiflora incarnata L. Phytother Res 2011; 25: 838-843
    CrossrefPubMedGoogle Scholar
  • 28 Li R, Wang X, Qin T, Qu R, Ma S. Apigenin ameliorates chronic mild stress-induced depressive behavior by inhibiting interleukin-1beta production and NLRP3 inflammasome activation in the rat brain. Behav Brain Res 2016; 296: 318-325
    CrossrefPubMedGoogle Scholar
  • 29 Liu Y, Lan N, Ren J, Wu Y, Wang ST, Huang XF, Yu Y. Orientin improves depression-like behavior and BDNF in chronic stressed mice. Mol Nutr Food Res 2015; 59: 1130-1142
    CrossrefPubMedGoogle Scholar
  • 30 Mandery K, Bujok K, Schmidt I, Keiser M, Siegmund W, Balk B, Konig J, Fromm MF, Glaeser H. Influence of the flavonoids apigenin, kaempferol, and quercetin on the function of organic anion transporting polypeptides 1A2 and 2B1. Biochem Pharmacol 2010; 80: 1746-1753
    CrossrefPubMedGoogle Scholar
  • 31 Houghton PJ. The scientific basis for the reputed activity of Valerian. J Pharm Pharmacol 1999; 51: 505-512
    CrossrefPubMedGoogle Scholar
  • 32 Murphy K, Kubin ZJ, Shepherd JN, Ettinger RH. Valeriana officinalis root extracts have potent anxiolytic effects in laboratory rats. Phytomedicine 2010; 17: 674-678
    CrossrefPubMedGoogle Scholar
  • 33 Trauner G, Khom S, Baburin I, Benedek B, Hering S, Kopp B. Modulation of GABAA receptors by valerian extracts is related to the content of valerenic acid. Planta Med 2008; 74: 19-24
    Article in Thieme ConnectPubMedGoogle Scholar
  • 34 Harper JN, Wright SH. Multiple mechanisms of ligand interaction with the human organic cation transporter, OCT2. Am J Physiol Renal Physiol 2013; 304: F56-F67
    CrossrefPubMedGoogle Scholar
  • 35 Koenen A, Kock K, Keiser M, Siegmund W, Kroemer HK, Grube M. Steroid hormones specifically modify the activity of organic anion transporting polypeptides. Eur J Pharm Sci 2012; 47: 774-780
    CrossrefPubMedGoogle Scholar
  • 36 Grube M, Kock K, Karner S, Reuther S, Ritter CA, Jedlitschky G, Kroemer HK. Modification of OATP2B1-mediated transport by steroid hormones. Mol Pharmacol 2006; 70: 1735-1741
    CrossrefPubMedGoogle Scholar
  • 37 Gazola AC, Costa GM, Zucolotto SM, Castellanos L, Ramos FA, de Lima TCM, Schenkel EP. The sedative activity of flavonoids from Passiflora quadrangularis is mediated through the GABAergic pathway. Biomed Pharmacother 2018; 100: 388-393
    CrossrefPubMedGoogle Scholar
  • 38 Gadioli IL, da Cunha MSB, de Carvalho MVO, Costa AM, Pineli LLO. A systematic review on phenolic compounds in Passiflora plants: Exploring biodiversity for food, nutrition, and popular medicine. Crit Rev Food Sci Nutr 2018; 58: 785-807
    CrossrefPubMedGoogle Scholar
  • 39 van Praag H, Lucero MJ, Yeo GW, Stecker K, Heivand N, Zhao C, Yip E, Afanador M, Schroeter H, Hammerstone J, Gage FH. Plant-derived flavanol (−)epicatechin enhances angiogenesis and retention of spatial memory in mice. J Neurosci 2007; 27: 5869-5878
    CrossrefPubMedGoogle Scholar
  • 40 Angelino D, Berhow M, Ninfali P, Jeffery EH. Caecal absorption of vitexin-2-O-xyloside and its aglycone apigenin, in the rat. Food Funct 2013; 4: 1339-1345
    CrossrefPubMedGoogle Scholar
  • 41 Reddy DS. Neurosteroids: endogenous role in the human brain and therapeutic potentials. Prog Brain Res 2010; 186: 113-137
    CrossrefPubMedGoogle Scholar
  • 42 Giatti S, Diviccaro S, Serafini MM, Caruso D, Garcia-Segura LM, Viviani B, Melcangi RC. Sex differences in steroid levels and steroidogenesis in the nervous system: Physiopathological role. Front Neuroendocrinol 2020; 56: 100804
    CrossrefPubMedGoogle Scholar
  • 43 Koenen A, Kroemer HK, Grube M, Meyer zu Schwabedissen HE. Current understanding of hepatic and intestinal OATP-mediated drug-drug interactions. Expert Rev Clin Pharmacol 2011; 4: 729-742
    CrossrefPubMedGoogle Scholar
  • 44 Glaeser H, Bailey DG, Dresser GK, Gregor JC, Schwarz UI, McGrath JS, Jolicoeur E, Lee W, Leake BF, Tirona RG, Kim RB. Intestinal drug transporter expression and the impact of grapefruit juice in humans. Clin Pharmacol Ther 2007; 81: 362-370
    CrossrefPubMedGoogle Scholar
  • 45 Drozdzik M, Groer C, Penski J, Lapczuk J, Ostrowski M, Lai Y, Prasad B, Unadkat JD, Siegmund W, Oswald S. Protein abundance of clinically relevant multidrug transporters along the entire length of the human intestine. Mol Pharm 2014; 11: 3547-3555
    CrossrefPubMedGoogle Scholar
  • 46 Neuhaus W, Trauner G, Gruber D, Oelzant S, Klepal W, Kopp B, Noe CR. Transport of a GABAA receptor modulator and its derivatives from Valeriana officinalis L. s. l. across an in vitro cell culture model of the blood-brain barrier. Planta Med 2008; 74: 1338-1344
    Article in Thieme ConnectPubMedGoogle Scholar
  • 47 Hubeny A, Keiser M, Oswald S, Jedlitschky G, Kroemer HK, Siegmund W, Grube M. Expression of organic anion transporting polypeptide 1A2 in red blood cells and its potential impact on antimalarial therapy. Drug Metab Dispos 2016; 44: 1562-1568
    CrossrefPubMedGoogle Scholar