Potent Inhibitors of Organic Anion Transporters 1 and 3 From Natural Compounds and Their Protective Effect on Aristolochic Acid Nephropathy

2020 ◽  
Vol 175 (2) ◽  
pp. 279-291
Author(s):  
Caiyu Li ◽  
Xue Wang ◽  
Yajuan Bi ◽  
Heshui Yu ◽  
Jing Wei ◽  
...  
Keyword(s):  
Drug Interactions ◽  
Natural Compound ◽  
Aristolochic Acid ◽  
Organic Anion ◽  
Critical Role ◽  
Natural Compounds ◽  
Organic Anion Transporters ◽  
Herbal Products ◽  
Anion Transporters

Abstract Organic anion transporters 1 and 3 (OAT1 and OAT3) play a critical role in renal drug-drug interactions and are involved in the nephrotoxicity of many anionic xenobiotics. To date, relatively little is known about the interaction of natural compounds with OAT1 and OAT3. Of the 270 natural compounds screened in the present study, 21 compounds inhibited OAT1 and 45 compounds inhibited OAT3. Further concentration-dependent studies identified 7 OAT1 inhibitors and 10 OAT3 inhibitors with IC50 values of <10 μM, and most of them were flavonoids, the most commonly ingested polyphenolic compounds in the diet and herbal products. Computational modeling of OAT1 and OAT3 revealed the important residues for the recognition of inhibitors. The two strong OAT inhibitors, namely wedelolactone and wogonin, were evaluated for their in vivo interactions with the OAT substrate aristolochic acid I (AAI), a natural compound causing aristolochic acid-induced nephropathy (AAN) in many species. The cytotoxicity of AAI increased in two OAT-overexpressing cell lines, with more cytotoxicity in OAT1-overexpressing cells, suggesting a more important role of OAT1 than OAT3 in AAN. Both wedelolactone and wogonin markedly increased serum AAI concentrations in AAI-treated rats and ameliorated kidney injuries in AAI-treated mice. To conclude, the present findings are of significant value in understanding natural compound-drug interactions and provide a natural source for developing treatments for AAN.

Critical Role of Organic Anion Transporters 1 and 3 in Kidney Accumulation and Toxicity of Aristolochic Acid I

2011 ◽  
Vol 8 (6) ◽  
pp. 2183-2192 ◽  
Author(s):  
Xiang Xue ◽  
Li-Kun Gong ◽  
Kazuya Maeda ◽  
Yang Luan ◽  
Xin-Ming Qi ◽  
...  
Keyword(s):  
Aristolochic Acid ◽  
Organic Anion ◽  
Critical Role ◽  
Organic Anion Transporters ◽  
Anion Transporters ◽  
Aristolochic Acid I

EVALUATION OF DRUG-DRUG INTERACTION IN THE HEPATOBILIARY AND RENAL TRANSPORT OF DRUGS

2005 ◽  
Vol 45 (1) ◽  
pp. 689-723 ◽  
Author(s):  
Yoshihisa Shitara ◽  
Hitoshi Sato ◽  
Yuichi Sugiyama
Keyword(s):  
Drug Interactions ◽  
Organic Anion ◽  
Renal Transport ◽  
Drug Metabolizing Enzymes ◽  
Organic Anion Transporters ◽  
Organic Anion Transporting Polypeptides ◽  
Metabolizing Enzymes ◽  
Anion Transporters ◽  
Degree Of Overlap

Recent studies have revealed the import role played by transporters in the renal and hepatobiliary excretion of many drugs. These transporters exhibit a broad substrate specificity with a degree of overlap, suggesting the possibility of transporter-mediated drug-drug interactions with other substrates. This review is an overview of the roles of transporters and the possibility of transporter-mediated drug-drug interactions. Among the large number of transporters, we compare the Ki values of inhibitors for organic anion transporting polypeptides (OATPs) and organic anion transporters (OATs) and their therapeutic unbound concentrations. Among them, cephalosporins and probenecid have the potential to produce clinically relevant OAT-mediated drug-drug interactions, whereas cyclosporin A and rifampicin may trigger OATP-mediated ones. These drugs have been reported to cause drug-drug interactions in vivo with OATs or OATP substrates, suggesting the possibility of transporter-mediated drug-drug interactions. To avoid adverse consequences of such transporter-mediated drug-drug interactions, we need to be more aware of the role played by drug transporters as well as those caused by drug metabolizing enzymes.

Developmental expression of renal organic anion transporters in rat kidney and its effect on renal secretion of phenolsulfonphthalein

2012 ◽  
Vol 302 (12) ◽  
pp. F1640-F1649 ◽  
Author(s):  
Maki Nomura ◽  
Hideyuki Motohashi ◽  
Hiroko Sekine ◽  
Toshiya Katsura ◽  
Ken-ichi Inui
Keyword(s):  
Protein Expression ◽  
Organic Anion ◽  
Immunohistochemical Analysis ◽  
Tubular Secretion ◽  
Organic Anion Transporters ◽  
Adult Rats ◽  
Anion Transporters ◽  
Anionic Drugs ◽  
Clearance Study

Organic anion transporters (OAT1 and OAT3) and multidrug resistance-associated proteins (MRP2 and MRP4) play important roles in anionic drug secretion in renal proximal tubules. Changes in the expression of such transporters are considered to affect the tubular secretion of anionic drugs. The purpose of this study was to elucidate the developmental changes in the expression of OAT1, OAT3, MRP2, and MRP4 and their effects on the tubular secretion of drugs. The mRNA level of each transporter was measured by real-time PCR, and the protein expression was evaluated by Western blotting and immunohistochemical analysis. In addition, the tubular secretion of phenolsulfonphthalein (PSP) in infant (postnatal day 14) and adult rats was estimated based on in vivo clearance study. The protein expression of organic anion transporters were very low at postnatal day 0 and gradually increased with age. In postnatal day 14 rats, the expression of OAT1 and OAT3 seemed to be at almost mature levels, while MRP2 and MRP4 seemed to be at immature levels. Immunohistochemical analysis in the kidney of postnatal day 0 rats revealed OATs on the basolateral membrane and MRPs on the brush-border membrane. At postnatal day 0, the distribution of these transporters was restricted to the inner cortical region, while after postnatal day 14, it was identical to that in adult kidney. An in vivo clearance study revealed that the tubular secretion of PSP was significantly lower in postnatal day 14 rats than adult rats. These results indicate that age-dependent changes in organic anion transporter expression affect the tubular secretion of anionic drugs in pediatric patients.

Molecular evidence for an involvement of organic anion transporters (OATs) in aristolochic acid nephropathy

Toxicology ◽  
2009 ◽  
Vol 264 (1-2) ◽  
pp. 74-79 ◽  
Author(s):  
Nadiya Bakhiya ◽  
Volker M. Arlt ◽  
Andrew Bahn ◽  
Gerhard Burckhardt ◽  
David H. Phillips ◽  
...  
Keyword(s):  
Aristolochic Acid ◽  
Organic Anion ◽  
Molecular Evidence ◽  
Organic Anion Transporters ◽  
Anion Transporters ◽  
Aristolochic Acid Nephropathy

Transport of cimetidine by flounder and human renal organic anion transporter 1

2003 ◽  
Vol 284 (3) ◽  
pp. F503-F509 ◽  
Author(s):  
Birgitta C. Burckhardt ◽  
Stefan Brai ◽  
Sönke Wallis ◽  
Wolfgang Krick ◽  
Natascha A. Wolff ◽  
...  
Keyword(s):  
Organic Anion ◽  
Human Kidney ◽  
Organic Anion Transporter ◽  
In Vivo Studies ◽  
Xenopus Laevis Oocytes ◽  
Organic Anion Transporters ◽  
Anion Transporters ◽  
Anion Transporter ◽  
Inward Currents

The H2-receptor antagonist cimetidine is efficiently excreted by the kidneys. In vivo studies indicated an interaction of cimetidine not only with transporters for basolateral uptake of organic cations but also with those involved in excretion of organic anions. We therefore tested cimetidine as a possible substrate of the organic anion transporters cloned from winter flounder (fROAT) and from human kidney (hOAT1). Uptake of [3H]cimetidine into fROAT-expressing Xenopus laevis oocytes exceeded uptake into control oocytes. At −60-mV clamp potential, 1 mM cimetidine induced an inward current, which was smaller than that elicited by 0.1 mM PAH. Cimetidine concentrations exceeding 0.1 mM decreased PAH-induced inward currents, indicating interaction with the same transporter. At pH 6.6, no current was seen with 0.1 mM cimetidine, whereas at pH 8.6 a current was readily detectable, suggesting preferential translocation of uncharged cimetidine by fROAT. Oocytes expressing hOAT1 also showed [3H]cimetidine uptake. These data reveal cimetidine as a substrate for fROAT/hOAT1 and suggest that organic anion transporters contribute to cimetidine excretion in proximal tubules.

scholarly journals Evaluation of para-Aminosalicylic Acid as a Substrate of Multiple Solute Carrier Uptake Transporters and Possible Drug Interactions with Nonsteroidal Anti-inflammatory Drugs In Vitro

2017 ◽  
Vol 61 (5) ◽  
Author(s):  
M. Masud Parvez ◽  
Ho Jung Shin ◽  
Jin Ah Jung ◽  
Jae-Gook Shin
Keyword(s):  
Drug Interactions ◽  
Organic Anion ◽  
Multidrug Resistant ◽  
Aminosalicylic Acid ◽  
Anion Transporters ◽  
Net Uptake ◽  
Inflammatory Drugs ◽  
Anti Inflammatory

ABSTRACT para-Aminosalicylic acid (PAS) is a second-line antituberculosis drug that has been used to treat multidrug-resistant and extensively drug-resistant tuberculosis for more than 60 years. Renal secretion and glomerular filtration are the major pathways for the elimination of PAS. We comprehensively studied PAS transport by using cell lines that overexpressed various transporters and found that PAS acts as a novel substrate of an organic anionic polypeptide (OATP1B1), organic cationic transporters (OCT1 and OCT2), and organic anion transporters (OAT1 and OAT3) but is not a substrate of any ATP-binding cassette (ABC) transporters. Net PAS uptake was measured, and the transport affinities (Km values) for OATP1B1, OCT1, OCT2, OAT1, and OAT3 were found to be 50.0, 20.3, 28.7, 78.1, and 100.1 μM, respectively. The net uptake rates suggested that renal OAT1 and OAT3 play relatively major roles in PAS elimination. The representative inhibitors rifampin for OATP1B1, probenecid for OAT1 and OAT3, and verapamil for OCT1 and OCT2 greatly inhibited PAS uptake, suggesting that PAS is dependent on multiple transporters for uptake. We also evaluated nonsteroidal anti-inflammatory drugs (NSAIDs), proton pump inhibitors (PPIs), and metformin for the inhibition of PAS uptake via these transporters. Half-maximal (50%) inhibitory concentrations (IC50s) were kinetically determined and used to predict the drug-drug interactions (DDIs) affecting these transporters' activity toward PAS. We found that rifampin, probenecid, ibuprofen, naproxen, cimetidine, and quinidine each exhibited a significant potential for in vivo DDIs with PAS. In this study, PAS was found to be a novel substrate of several transporters, and drugs that inhibit these transporters can reduce PAS elimination.

scholarly journals Optimal Methods of Antigen Retrieval for Organic Anion Transporters in Cryosections of the Rat Kidney

2009 ◽  
Vol 60 (1) ◽  
pp. 7-17 ◽  
Author(s):  
Hrvoje Brzica ◽  
Davorka Breljak ◽  
Marija Ljubojević ◽  
Daniela Balen ◽  
Vedran Micek ◽  
...  
Keyword(s):  
Rat Kidney ◽  
Organic Anion ◽  
Staining Intensity ◽  
Antigen Retrieval ◽  
Organic Anion Transporters ◽  
Optimal Methods ◽  
Anion Transporters ◽  
Pre Treatment

Optimal Methods of Antigen Retrieval for Organic Anion Transporters in Cryosections of the Rat KidneyTo localise antigens by immunocytochemistry (IC), the samples of tissues or cells are usually denatured by fixation, and either frozen and cryosectioned, or embedded in paraffin before sectioning. p-Formaldehyde (PFA; formalin) is a common fixative, which preserves antigenicity of proteins, but damages the tissue/cell morphology and "masks" the antibody binding sites (epitopes). In order to "unmask" epitopes, some kind of antigen retrieval (AR) is used. The aim of this study was: a) to find an optimal AR method in cryosections of in vivo PFA-fixed kidneys for organic anion transporters (Oat) that reside in the basolateral (Oat1, Oat3) and brush-border membrane (Oat2, Oat5) of the rat renal proximal tubules, and b) using optimal method, to compare IC staining of Oats in kidneys that had been PFA-fixed in vivo or in vitro. IC staining in untreated cryosections was compared with that following detergent treatment or microwave heating in citrate buffer of pH 3, pH 6, or pH 8, with or without alcohol pre-treatment. The preferred AR method for Oat1, Oat2, and Oat5 was heating of cryosections at pH 6, and for Oat3 heating at pH 3, without alcohol pre-treatment. Compared with tissue fixed in vivo, tissue fixed in vitro exhibited damaged tubule morphology, similar staining intensity of Oat1 and Oat3, and higher staining intensity of Oat2 and Oat5. We conclude that for optimal IC presentation, each Oat in the rat kidney has to be treated individually, with different fixation and AR approach.

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