scholarly journals Interaction of Anticancer Drugs with Human Organic Anion Transporter hOAT4

2019 ◽  
Vol 2019 ◽  
pp. 1-8 ◽  
Author(s):  
Chenchang Liu ◽  
Jinghui Zhang ◽  
Guofeng You
Keyword(s):  
Drug Interaction ◽  
Anticancer Drugs ◽  
Organic Anion ◽  
Inhibitory Effect ◽  
Organic Anion Transporter ◽  
Estrone Sulfate ◽  
Anion Transporters ◽  
Anion Transporter ◽  
Drug Drug Interaction ◽  
The Individual

Human organic anion transporter 4 (hOAT4) belongs to a family of multispecific organic anion transporters that play critical roles in the disposition of numerous drugs and therefore are the major sites for drug-drug interaction. Drug-drug interactions contribute significantly to the individual variation in drug response. hOAT4 is expressed in the kidney and placenta. In the current study, we examined the interaction of 36 anticancer drugs with hOAT4 in kidney COS-7 cells and placenta BeWo cells. Among the drugs tested, only epirubicin hydrochloride and dabrafenib mesylate exhibited > 50% cis-inhibitory effect, in COS-7 cells, on hOAT4-mediated uptake of estrone sulfate, a prototypical substrate for the transporter. The IC50values for epirubicin hydrochloride and dabrafenib mesylate were 5.24±0.95μM and 8.30±3.30μM, respectively. Dixon plot analysis revealed that inhibition by epirubicin hydrochloride was noncompetitive with aKi= 3μM whereas inhibition by dabrafenib mesylate was competitive with aKi= 4.26μM. Our results established that epirubicin hydrochloride and dabrafenib mesylate are inhibitors of hOAT4. Furthermore, by comparing our data with clinically relevant exposures of these drugs, we conclude that although the tendency for dabrafenib mesylate to cause drug-drug interaction through hOAT4 is insignificant in the kidney, the propensity for epirubicin hydrochloride to cause drug-drug interaction is high.

Renal human organic anion transporter 3 increases the susceptibility of lymphoma cells to bendamustine uptake

2015 ◽  
Vol 308 (4) ◽  
pp. F330-F338 ◽  
Author(s):  
Yohannes Hagos ◽  
Philip Hundertmark ◽  
Volodymyr Shnitsar ◽  
Venkata V. V. R. Marada ◽  
Gerald Wulf ◽  
...  
Keyword(s):  
Organic Anion ◽  
Inhibitory Effect ◽  
Organic Anion Transporter ◽  
Lymphoma Cells ◽  
Estrone Sulfate ◽  
Anion Transporters ◽  
Lymphatic Leukemia ◽  
Anion Transporter ◽  
Nephritic Syndrome ◽  
The Impact

Chronic lymphatic leukemia (CLL) is often associated with nephritic syndrome. Effective treatment of CLL by chlorambucil and bendamustine leads to the restoration of renal function. In this contribution, we sought to elucidate the impact of organic anion transporters (OATs) on the uptake of bendamustine and chlorambucil as a probable reason for the superior efficacy of bendamustine over chlorambucil in the treatment of CLL. We examined the effects of structural analogs of p-aminohippurate (PAH), melphalan, chlorambucil, and bendamustine, on OAT1-mediated [3H]PAH uptake and OAT3- and OAT4-mediated [3H]estrone sulfate (ES) uptake in stably transfected human embryonic kidney-293 cells. Melphalan had no significant inhibitory effect on any OAT, whereas chlorambucil reduced OAT1-, OAT3-, and OAT4-mediated uptake of PAH or ES down to 14.6%, 16.3%, and 66.0% of control, respectively. Bendamustine inhibited only OAT3-mediated ES uptake, which was reduced down to 14.3% of control cells, suggesting that it interacts exclusively with OAT3. The IC50 value for OAT3 was calculated to be 0.8 μM. Real-time PCR experiments demonstrated a high expression of OAT3 in lymphoma cell lines as well as primary CLL cells. OAT3-mediated accumulation of bendamustine was associated with reduced cell proliferation and an increased rate of apoptosis. We conclude that the high efficacy of bendamustine in treating CLL might be partly contributed to the expression of OAT3 in lymphoma cells and the high affinity of bendamustine for this transporter.

Renal Organic Anion Transporter-Mediated Drug-Drug Interaction between Gemcabene and Quinapril

2009 ◽  
Vol 330 (1) ◽  
pp. 191-197 ◽  
Author(s):  
Haodan Yuan ◽  
Bo Feng ◽  
Ying Yu ◽  
Jonathan Chupka ◽  
Jenny Y. Zheng ◽  
...  
Keyword(s):  
Drug Interaction ◽  
Organic Anion ◽  
Organic Anion Transporter ◽  
Anion Transporter ◽  
Drug Drug Interaction

scholarly journals Organic Anion Transporter 1B1: An Important Factor in Hepatic Thyroid Hormone and Estrogen Transport and Metabolism

Endocrinology ◽  
2008 ◽  
Vol 149 (9) ◽  
pp. 4695-4701 ◽  
Author(s):  
Wendy M. van der Deure ◽  
Edith C. H. Friesema ◽  
Frank Jan de Jong ◽  
Yolanda B. de Rijke ◽  
Frank H. de Jong ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Organic Anion ◽  
Organic Anion Transporter ◽  
Hepatic Transport ◽  
Transfected Cells ◽  
Estrone Sulfate ◽  
Anion Transporters ◽  
Anion Transporter ◽  
Metabolism Of Bilirubin

Sulfation is an important pathway in the metabolism of thyroid hormone and estrogens. Sulfation of estrogens is reversible by estrogen sulfatase, but sulfation of thyroid hormone accelerates its degradation by the type 1 deiodinase in liver. Organic anion transporters (OATPs) are capable of transporting iodothyronine sulfates such as T4 sulfate (T4S), T3S, and rT3S or estrogen sulfates like estrone sulfate (E1S), but the major hepatic transporter for these conjugates has not been identified. A possible candidate is OATP1B1 because model substrates for this transporter include the bilirubin mimic bromosulfophthalein (BSP) and E1S, and it is highly and specifically expressed in liver. Therefore, OATP1B1-transfected COS1 cells were studied by analysis of BSP, E1S, and iodothyronine sulfate uptake and metabolism. Two Caucasian populations (155 blood donors and 1012 participants of the Rotterdam Scan Study) were genotyped for the OATP1B1-Val174Ala polymorphism and associated with bilirubin, E1S, and T4S levels. OATP1B1-transfected cells strongly induced uptake of BSP, E1S, T4S, T3S, and rT3S compared with mock-transfected cells. Metabolism of iodothyronine sulfates by cotransfected type 1 deiodinase was greatly augmented in the presence of OATP1B1. OATP1B1-Val174 showed a 40% higher induction of transport and metabolism of these substrates than OATP1B1-Ala174. Carriers of the OATP1B1-Ala174 allele had higher serum bilirubin, E1S, and T4S levels. In conclusion, OATP1B1 is an important factor in hepatic transport and metabolism of bilirubin, E1S, and iodothyronine sulfates. OATP1B1-Ala174 displays decreased transport activity and thereby gives rise to higher bilirubin, E1S, and T4S levels in carriers of this polymorphism.

Impact of Organic Anion Transporter 3 (OAT3) on Bendamustine Uptake of Lymphoma Cells.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4184-4184
Author(s):  
Yohannes Hagos ◽  
Gerald G. Wulf ◽  
Vladimir Shnitsar ◽  
Philip Hundertmark ◽  
Shvangi Gupta ◽  
...  
Keyword(s):  
Cell Lines ◽  
Organic Anion ◽  
Inhibitory Effect ◽  
Lymphoma Cell ◽  
Organic Anion Transporter ◽  
Hek293 Cells ◽  
Sulfate Uptake ◽  
Lymphoma Cells ◽  
Estrone Sulfate ◽  
Anion Transporter

Abstract One main problem of tumor therapy is the resistance of malignant cells to cytostatics due to high expression of efflux transporters. Whereas the role of these efflux transporters for tumor cell resistance is well established, little is known about uptake transporters, which may increase the sensibility of tumor cells for cytostatics. In the present study we addressed the interaction of cytostatics established for the treatment of lymphoma, namely melphalan, chlorambucil or bendamustine with human Organic Anion Transporter (OATs), which belong to the Solute carrier (SLC) gene family. We selected these cytostatics, because they show structural similarity to p-aminohyppurate (PAH), the model substrate of OATs. OATs are mainly expressed in the kidney, where they are responsible for the excretion of endogenous and exogenous organic anions like urate or various drugs e.g. diuretics. Initially, we examined the cis-inhibitory effect of melphalan, chlorambucil and bendamustine on OAT1-mediated [3H]PAH uptake as well as OAT3- and OAT4- mediated [3H]estrone sulfate uptake in HEK293 cells, which were stably transfected with these transporters. Melphalan did not show any significant inhibitory effect on all tested OATs. 100 μM chlorambucil reduced OAT1-, OAT3- and OAT4-mediated uptake of PAH or estrone sulfate down to 14.6 ± 0.17%, 16.3 ± 4.0% and 66.0 ± 1.4%, respectively. 100 μM bendamustine inhibited only OAT3-mediated estrone sulfate uptake up to 91.9 ± 0.5% compared to control cells. OAT1- or OAT4- facilitated transport of PAH and estrone sulfate remained unchanged by bendamustine, suggesting that bendamustine interacts exclusively with OAT3. To determine the affinity of OAT3 for bendamustine and chlorambucil, we performed concentration dependent inhibition of OAT3-mediated estrone sulfate uptake and calculated the Ki values for both cytostatics. Dixon-Plot evaluation confirmed a competitive inhibition of OAT3 by bendamustine as well as chlorambucil. The results demonstrated higher affinity of OAT3 for bendamustine with a Ki value of 2.7 μM than for chlorambucil, showing a Ki value of 38.2 μM. To elucidate the expression of OATs in lymphoma cell lines, we performed RT-PCR experiments. Our data demonstrate high expression of OAT3 in all cell lines compared to lymphocytes isolated from a normal person. No expression of OAT1 and OAT4 was observed any lymphoma cell lines. The expression of OAT3 in B-cell lymphoma cell lines Karpas, Raji, SudHL4 and T-cell lymphoma cell lines L428, Jurkat and Hut78 was quantified by real time PCR. The highest expression of OAT3 was observed in the order Jurkat>Hut78>SudHL4>L428>Raji>Karpas. The expression of OAT3 was confirmed by real time PCR in four patients with chronic lymphocytic leukamia. OAT3- dependent cytostatic effects of bendamustine was examined by [3H] thymidine incorporation. 30 min incubation of OAT3-expressing HEK293 cells with 10, 50 or 100 μM bendamustine significantly reduced the proliferation of transfected versus non-transfected cells. We conclude that the molecular background for the cytostatic efficiency of bendamustine in lymphoma cells is due to 1) the expression of OAT3 in lymphoma cells and 2) a the high affinity of OAT3 for bendamustine.

Human organic anion transporter OAT1 is not responsible for glutathione transport but mediates transport of glutamate derivatives

2013 ◽  
Vol 304 (4) ◽  
pp. F403-F409 ◽  
Author(s):  
Yohannes Hagos ◽  
Gerhard Burckhardt ◽  
Birgitta C. Burckhardt
Keyword(s):  
Organic Anion ◽  
Organic Anion Transporter ◽  
Hek293 Cells ◽  
Toxic Substances ◽  
Organic Anion Transporters ◽  
Estrone Sulfate ◽  
Anion Transporters ◽  
Anion Transporter ◽  
Cellular Integrity ◽  
High Concentrations

Due to their clearance function, the kidneys are exposed to high concentrations of oxidants and potentially toxic substances. To maintain cellular integrity, renal cells have to be protected by sufficient concentrations of the antioxidant glutathione (GSH). We tested whether GSH or its precursors are taken up by human organic anion transporters 1 (OAT1) and 3 (OAT3) stably expressed in HEK293 cells. GSH did not inhibit uptake of p-aminohippurate (PAH) or of estrone sulfate (ES) in OAT3-transfected HEK293 cells. In OAT1-transfected cells, GSH reduced the uptake of PAH marginally. Among the GSH constituent amino acids, glutamate, cysteine, and glycine, only glutamate inhibited OAT1, but labeled glutamate was not taken up by a probenecid-inhibitable transport system. Thus OAT1 binds glutamate but is unable to translocate it. The GSH precursor dipeptide, cysteinyl glycine (cysgly), and the glutamate derivative N-acetyl glutamate (NAG), inhibited uptake of PAH when present in the medium and trans-stimulated uptake of PAH from the intracellular side, indicating that they are hitherto unrecognized transported substrates of OAT1. N-acetyl aspartate weakly interacted with OAT1, but aspartate did not. NAG inhibited also OAT3, albeit with much lower affinity compared with OAT1, and glutamate did not interact with OAT3 at all. Taken together, human OAT3 and OAT1 cannot be involved in renal GSH extraction from the blood. However, OAT1 could support intracellular GSH synthesis by taking up cysteinyl glycine.

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