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

Planta Medica ◽  
2021 ◽  
Author(s):  
Anima M. Schäfer ◽  
Pierrine M. Gilgen ◽  
Clara Spirgi ◽  
Olivier Potterat ◽  
Henriette E. Meyer zu Schwabedissen
Keyword(s):  
Organic Anion ◽  
Dehydroepiandrosterone Sulfate ◽  
Valeriana Officinalis ◽  
Organic Anion Transporting Polypeptides ◽  
Organic Anion Transporting Polypeptide ◽  
Sulfated Steroids ◽  
Valerenic Acid ◽  
Passiflora Incarnata ◽  
Uptake Transporters ◽  
Darby Canine Kidney

AbstractHerbal 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.

scholarly journals A novel human organic anion transporting polypeptide localized to the basolateral hepatocyte membrane

2000 ◽  
Vol 278 (1) ◽  
pp. G156-G164 ◽  
Author(s):  
Jörg König ◽  
Yunhai Cui ◽  
Anne T. Nies ◽  
Dietrich Keppler
Keyword(s):  
Human Liver ◽  
Organic Anion ◽  
Basolateral Membrane ◽  
Dehydroepiandrosterone Sulfate ◽  
Hek293 Cells ◽  
Base Pairs ◽  
Organic Anion Transporting Polypeptide ◽  
Mdckii Cells ◽  
Menten Constant ◽  
Darby Canine Kidney

We cloned and expressed a new organic anion transporting polypeptide (OATP), termed human OATP2, (OATP-C, LST-1; symbol SLC21A6), involved in the uptake of various lipophilic anions into human liver. The cDNA encoding OATP2 comprised 2073 base pairs, corresponding to a protein of 691 amino acids, which were 44% identical to the known human OATP. An antibody directed against the carboxy terminus localized OATP2 to the basolateral membrane of human hepatocytes. Northern blot analysis indicated a strong expression of OATP2 only in human liver. Transport mediated by recombinant OATP2 and its localization were studied in stably transfected Madin-Darby canine kidney strain II (MDCKII) and HEK293 cells. Confocal microscopy localized recombinant OATP2 protein to the lateral membrane of MDCKII cells. Substrates included 17β-glucuronosyl estradiol, monoglucuronosyl bilirubin, dehydroepiandrosterone sulfate, and cholyltaurine. 17β-Glucuronosyl estradiol was a preferred substrate, with a Michaelis-Menten constant value of 8.2 μM; its uptake was Na+ independent and was inhibited by sulfobromophthalein, with a inhibition constant value of 44 nM. Our results indicate that OATP2 is important for the uptake of organic anions, including bilirubin conjugates and sulfobromophthalein, in human liver.

scholarly journals Expression and Function of Organic Anion Transporting Polypeptides in the Human Brain: Physiological and Pharmacological Implications

Pharmaceutics ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 834
Author(s):  
Anima M. Schäfer ◽  
Henriette E. Meyer zu Schwabedissen ◽  
Markus Grube
Keyword(s):  
Organic Anion ◽  
Physiological Role ◽  
Point Of View ◽  
Efflux Transporters ◽  
Organic Anion Transporting Polypeptides ◽  
Current State ◽  
P Glycoprotein ◽  
The Central Nervous System ◽  
And Function ◽  
Uptake Transporters

The central nervous system (CNS) is an important pharmacological target, but it is very effectively protected by the blood–brain barrier (BBB), thereby impairing the efficacy of many potential active compounds as they are unable to cross this barrier. Among others, membranous efflux transporters like P-Glycoprotein are involved in the integrity of this barrier. In addition to these, however, uptake transporters have also been found to selectively uptake certain compounds into the CNS. These transporters are localized in the BBB as well as in neurons or in the choroid plexus. Among them, from a pharmacological point of view, representatives of the organic anion transporting polypeptides (OATPs) are of particular interest, as they mediate the cellular entry of a variety of different pharmaceutical compounds. Thus, OATPs in the BBB potentially offer the possibility of CNS targeting approaches. For these purposes, a profound understanding of the expression and localization of these transporters is crucial. This review therefore summarizes the current state of knowledge of the expression and localization of OATPs in the CNS, gives an overview of their possible physiological role, and outlines their possible pharmacological relevance using selected examples.

scholarly journals Role of OAT4 in Uptake of Estriol Precursor 16α-Hydroxydehydroepiandrosterone Sulfate Into Human Placental Syncytiotrophoblasts From Fetus

Endocrinology ◽  
2015 ◽  
Vol 156 (7) ◽  
pp. 2704-2712 ◽  
Author(s):  
Masatoshi Tomi ◽  
Hiromi Eguchi ◽  
Mayuko Ozaki ◽  
Tomohiro Tawara ◽  
Sachika Nishimura ◽  
...  
Keyword(s):  
Fetal Liver ◽  
Organic Anion ◽  
Dehydroepiandrosterone Sulfate ◽  
Cellular Level ◽  
Organic Anion Transporter ◽  
Organic Anion Transporting Polypeptide ◽  
Anion Transporter ◽  
Basal Plasma ◽  
Good Agreement

Estriol biosynthesis in human placenta requires the uptake of a fetal liver-derived estriol precursor, 16α-hydroxydehydroepiandrosterone sulfate (16α-OH DHEAS), by placental syncytiotrophoblasts at their basal plasma membrane (BM), which faces the fetal circulation. The aim of this work is to identify the transporter(s) mediating 16α-OH DHEAS uptake at the fetal side of syncytiotrophoblasts by using human placental BM-enriched vesicles and to examine the contribution of the putative transporter to estriol synthesis at the cellular level, using choriocarcinoma JEG-3 cells. Organic anion transporter (OAT)-4 and organic anion transporting polypeptide 2B1 proteins were enriched in human placental BM vesicles compared with crude membrane fraction. Uptake of [3H]16α-OH DHEAS by BM vesicles was partially inhibited in the absence of sodium but was significantly increased in the absence of chloride and after preloading glutarate. Uptake of [3H]16α-OH DHEAS by BM vesicles was significantly inhibited by OAT4 substrates such as dehydroepiandrosterone sulfate, estrone-3-sulfate, and bromosulfophthalein but not by cyclosporin A, tetraethylammonium, p-aminohippuric acid, or cimetidine. These characteristics of vesicular [3H]16α-OH DHEAS uptake are in good agreement with those of human OAT4-transfected COS-7 cells as well as forskolin-differentiated JEG-3 cells. Estriol secretion from differentiated JEG-3 cells was detected when the cells were incubated with 16α-OH DHEAS for 8 hours but was inhibited in the presence of 50 μM bromosulfophthalein. Our results indicate that OAT4 at the BM of human placental syncytiotrophoblasts plays a predominant role in the uptake of 16α-OH DHEAS for placental estriol synthesis.

scholarly journals Interaction of Hydroxychloroquine with Pharmacokinetically Important Drug Transporters

Pharmaceutics ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 919
Author(s):  
Johanna Weiss ◽  
Gzona Bajraktari-Sylejmani ◽  
Walter E. Haefeli
Keyword(s):  
Cell Lines ◽  
Drug Transporters ◽  
Organic Anion ◽  
Parental Cell ◽  
Cancer Resistance ◽  
Glycoprotein P ◽  
Organic Anion Transporting Polypeptide ◽  
Aryl Hydrocarbon ◽  
Mrna Induction ◽  
Uptake Transporters

(1) Background: Hydroxychloroquine is used to treat malaria and autoimmune diseases, and its potential use against COVID-19 is currently under investigation. Thus far, information on interactions of hydroxychloroquine with drug transporters mediating drug-drug interactions is limited. We assessed the inhibition of important efflux (P-glycoprotein (P-gp), breast cancer resistance protein (BCRP)) and uptake transporters (organic anion transporting polypeptide (OATP)-1B1, OATP1B3, OATP2B1) by hydroxychloroquine, tested its P-gp and BCRP substrate characteristics, and evaluated the induction of pharmacokinetically relevant genes regulated by the nuclear pregnane X (PXR) (CYP3A4, ABCB1) and aryl hydrocarbon receptor (AhR) (CYP1A1, CYP1A2). (2) Methods: Transporter inhibition was evaluated in transporter over-expressing cell lines using fluorescent probe substrates. P-gp and BCRP substrate characteristics were assessed by comparing growth inhibition of over-expressing and parental cell lines. Possible mRNA induction was analysed in LS180 cells by quantitative real-time PCR. (3) Results: Hydroxychloroquine did not inhibit BCRP or the OATPs tested but inhibited P-gp at concentrations exceeding 10 µM. P-gp overexpressing cells were 5.2-fold more resistant to hydroxychloroquine than control cells stressing its substrate characteristics. Hydroxychloroquine did not induce genes regulated by PXR or AhR. (4) Conclusions: This is the first evidence that hydroxychloroquine’s interaction potential with drug transporters is low, albeit bioavailability of simultaneously orally administered P-gp substrates might be increased by hydroxychloroquine.

scholarly journals Metabolism of Dehydroepiandrosterone Sulfate and Estrone-Sulfate by Human Platelets

2012 ◽  
pp. 381-388 ◽  
Author(s):  
A. GARRIDO ◽  
Y. MUÑOZ ◽  
W. SIERRALTA ◽  
L. VALLADARES
Keyword(s):  
Organic Anion ◽  
Dehydroepiandrosterone Sulfate ◽  
Human Platelets ◽  
Steroid Sulfatase ◽  
Organic Anion Transporting Polypeptide ◽  
Estrone Sulfate ◽  
High Affinity ◽  
Sulfatase Activity ◽  
17Β Estradiol ◽  
Estrone Sulphate

The aim of the present research was to study the uptake of DHEAS, and to establish the intracrine capacity of human platelets to produce sex steroid hormones. The DHEAS transport was evaluated through the uptake of [3H]-DHEAS in the presence or absence of different substrates through the organic anion transporting polypeptide (OATP) family. The activity of sulfatase enzyme was evaluated, and the metabolism of DHEAS was measured by the conversion of [3H]-DHEAS to [3H]-androstenedione, [3H]-testosterone, [3H]-estrone and [3H]-17β-estradiol. Results indicated the existence in the plasma membrane of an OATP with high affinity for DHEAS and estrone sulphate (E1S). The platelets showed the capacity to convert DHEAS to active DHEA by the steroid-sulfatase activity. The cells resulted to be a potential site for androgens production, since they have the capacity to produce androstenedione and testosterone; in addition, they reduced [3H]-estrone to [3H]-17β-estradiol. This is the first demonstration that human platelets are able to import DHEAS and E1S using the OATP family and to convert DHEAS to active DHEA, and to transform E1S to 17β-estradiol.

scholarly journals Prediction of Drug-Induced Hyperbilirubinemia by In Vitro Testing

Pharmaceutics ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 755
Author(s):  
Péter Tátrai ◽  
Péter Krajcsi
Keyword(s):  
Organic Anion ◽  
The Body ◽  
In Vitro Assays ◽  
Current Evidence ◽  
Drug Induced ◽  
Organic Anion Transporting Polypeptide ◽  
Resistance Protein ◽  
Clinically Significant ◽  
Uptake Transporters

Bilirubin, the end product of heme catabolism, is produced continuously in the body and may reach toxic levels if accumulates in the serum and tissues; therefore, a highly efficient mechanism evolved for its disposition. Normally, unconjugated bilirubin enters hepatocytes through the uptake transporters organic anion transporting polypeptide (OATP) 1B1 and 1B3, undergoes glucuronidation by the Phase II enzyme UDP glucuronosyltransferase 1A1 (UGT1A1), and conjugated forms are excreted into the bile by the canalicular export pump multidrug resistance protein 2 (MRP2). Any remaining conjugated bilirubin is transported back to the blood by MRP3 and passed on for uptake and excretion by downstream hepatocytes or the kidney. The bile salt export pump BSEP as the main motor of bile flow is indirectly involved in bilirubin disposition. Genetic mutations and xenobiotics that interfere with this machinery may impede bilirubin disposition and cause hyperbilirubinemia. Several pharmaceutical compounds are known to cause hyperbilirubinemia via inhibition of OATP1Bs, UGT1A1, or BSEP. Herein we briefly review the in vitro prediction methods that serve to identify drugs with a potential to induce hyperbilirubinemia. In vitro assays can be deployed early in drug development and may help to minimize late-stage attrition. Based on current evidence, drugs that behave as mono- or multispecific inhibitors of OATP1B1, UGT1A1, and BSEP in vitro are at risk of causing clinically significant hyperbilirubinemia. By integrating inhibition data from in vitro assays, drug serum concentrations, and clinical reports of hyperbilirubinemia, predictor cut-off values have been established and are provisionally suggested in this review. Further validation of in vitro readouts to clinical outcomes is expected to enhance the predictive power of these assays.

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