Interaction of human organic anion transporter 2 (OAT2) and sodium taurocholate cotransporting polypeptide (NTCP) with antineoplastic drugs

Marada, Venkata V.V.R.; Flörl, Saskia; Kühne, Annett; Müller, Judith; Burckhardt, Gerhard; Hagos, Yohannes

doi:10.1016/j.phrs.2014.11.002

Cited by 30 publications

(22 citation statements)

References 39 publications

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“…In the present study the estimated real K m ‐value of OAT2 was 50–150 μM for cAMP and 100–200 μM for cGMP. The present K m ‐value for cGMP transport is in close correspondence with the values reported for HEK 293 cells lines with overexpression of OAT2‐tv1, 88 μM (Cropp et al, ) and 101 μM (Marada et al, ). However, the impact of the other biokinetic components (synthesis and hydrolysis) remains to be answered.…”

Section: Discussionsupporting

confidence: 91%

“…hOAT2 has come into focus with regard to cellular uptake of cGMP (Cropp et al, 2008;Marada et al, 2015). The affinity (K m -values of 90-100 μM) reported for hOAT2 transfected HEK293 cells was clearly higher than that calculated based on a previous study on uptake to intact hRBC (K m -values of 3-5 mM) (Flo et al, 1995).…”

mentioning

confidence: 82%

“…These proteins were also expressed in hRBC (Boadu & Sager, ; Jedlitschky et al, ; Klokouzas, Wu, van Veen, Barrand, & Hladky, ; Wu, Klokouzas, Hladky, Ambudkar, & Barrand, ). Later, hOAT2 has come into focus with regard to cellular uptake of cGMP (Cropp et al, ; Marada et al, ). The affinity ( K m ‐values of 90–100 μM) reported for hOAT2 transfected HEK293 cells was clearly higher than that calculated based on a previous study on uptake to intact hRBC ( K m ‐values of 3–5 mM) (Flo et al, ).…”

Section: Introductionmentioning

confidence: 99%

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The role of OAT2 (SLC22A7) in the cyclic nucleotide biokinetics of human erythrocytes

Sager

Smaglyukova

Fuskevaag

2018

Journal Cellular Physiology

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The present study was conducted to characterise the transporter(s) responsible for the uptake of cyclic nucleotides to human erythrocytes. Western blotting showed that hRBC expressed OAT2 (SLC22A7), but detection of OAT1 (SLC22A6), or OAT3 (SLC22A8) was not possible. Intact hRBC were employed to clarify the simultaneous cyclic nucleotide egression and uptake. Both these opposing processes were studied. The Km‐values for high affinity efflux was 3.5 ± 0.1 and 39.4 ± 5.7 μM for cGMP and cAMP, respectively. The respective values for low affinity efflux were 212 ± 11 and 339 ± 42 μM. The uptake was characterised with apparently low affinity and similar Km‐values for cGMP (2.2 mM) and cAMP (0.89 mM). Using an iterative approach in order to balance uptake with efflux, the predicted real Km‐values for uptake were 100–200 μM for cGMP and 50–150 μM for cAMP. The established OAT2‐substrate indomethacin showed a competitive interaction with cyclic nucleotide uptake. Creatinine, also an OAT2 substrate, showed saturable uptake with a Km of 854 ± 98 μM. Unexpectedly, co‐incubation with cyclic nucleotides showed an uncompetitive inhibition. The observed Km‐values were 399 ± 44 and 259 ± 30 μM for creatinine, in the presence of cGMP and cAMP, respectively. Finally, the OAT1‐substrate para‐aminohippurate (PAH) showed some uptake (Km‐value of 2.0 ± 0.4 mM) but did not interact with cyclic nucleotide or indomethacin transport.

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Section: Discussionsupporting

confidence: 91%

mentioning

confidence: 82%

Section: Introductionmentioning

confidence: 99%

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The role of OAT2 (SLC22A7) in the cyclic nucleotide biokinetics of human erythrocytes

Sager

Smaglyukova

Fuskevaag

2018

Journal Cellular Physiology

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“…In addition to the chemotherapeutic agents such as docetaxel, the OAT2 transporter participates in the excretion of many other types of drugs including nonsteroidal anti-inflammatory drugs, angiotensinconverting enzyme inhibitors, and antibiotics (Russel et al, 2002;Cutler and Choo, 2011;Marada et al, 2015). Genetic deficiency of OAT2 has been linked to the alterations (e.g., reduced urinary excretion and higher level of circulating drug) in disposition of these drugs (Russel et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

Liver Receptor Homolog-1 Regulates Organic Anion Transporter 2 and Docetaxel Pharmacokinetics

Zhang

Guo

et al. 2018

Drug Metab Dispos

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Organic anion transporter 2 (OAT2/SLC22A7) is an uptake transporter that plays an important role in drug disposition. Here, we investigate a potential role of liver receptor homolog-1 (Lrh-1) in regulation of Oat2 and docetaxel pharmacokinetics. Hepatoma cells (Hepa1-6 and HepG2 cells) were transfected with Lrh-1/LRH-1 expression vector or siRNA. The relative mRNA and protein levels of Oat2/OAT2 in the cells or livers of Lrh-1 mice were determined by qPCR and Western blotting, respectively. Transcriptional regulation of Oat2/OAT2 by Lrh-1/LRH-1 was investigated using luciferase reporter, mobility shift, and chromatin immunoprecipitation (ChIP) assays. Pharmacokinetic studies were performed with wild-type (Lrh-1) and Lrh-1 mice after intraperitoneal injection of docetaxel. Overexpression of Lrh-1 in Hepa1-6 cells led to significant increases in Oat2 mRNA and protein. Consistently, Lrh-1 knockdown caused decreases in Oat2 mRNA and protein, as well as reduced cellular uptake of PGE2, a prototypical substrate of Oat2. Similarly, an activation effect of LRH-1 on OAT2 expression was observed in HepG2 cells. In addition, the levels of Oat2 mRNA and protein were markedly reduced in Lrh-1 mice. Lrh-1/LRH-1 induced the transcription of Oat2/OAT2 in luciferase reporter assays. Truncation analysis revealed a potential Lrh-1 response element (-716- to -702-bp) in Oat2 promoter. Direct binding of Lrh-1 to this response element was confirmed by mobility shift and ChIP assays. Furthermore, systemic exposure of docetaxel was upregulated in Lrh-1 mice due to reduced hepatic uptake. In conclusion, Lrh-1 transcriptionally regulates Oat2, thereby impacting tissue uptake and pharmacokinetics of Oat2 substrates.

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“…Like OAT1 and OAT3, OAT2 can accommodate a variety of organic anions and indeed has also been shown to transport a number of pharmacologically active agents. OAT2 has been increasingly recognized in terms of its role in drug disposition (Table 2) (Sun et al, 2001;Kobayashi et al, 2005a), H-2 receptor antagonists (cimetidine and ranitidine) (Tahara et al, 2005), diuretics (bumetanide) (Kobayashi et al, 2005a), nonsteroidal anti-inflammatory drugs (e.g., diclofenac) (Zhang et al, 2016), topoisomerase inhibitor (irinotecan) (Marada et al, 2015), and endogenous prostaglandins and hormones (e.g., prostaglandin E 2 , prostaglandin F 2 , DHEA sulfate, and E3S) (Enomoto et al, 2002b;Kobayashi et al, 2005aKobayashi et al, , 2014Jia et al, 2015) (Table 2). OAT2 has also been identified as a candidate diclofenac b-Dglucuronide transporter (Zhang et al, 2016).…”

Section: Relatively Well Understood Aspects Of Oat2mentioning

confidence: 99%

Organic Anion Transporter 2: An Enigmatic Human Solute Carrier

Shen¹,

Lai²,

Rodrigues³

2016

Drug Metab Dispos

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As a member of the solute carrier 22A (SLC22A) family, organic anion transporter 2 (OAT2; SLC22A7) is emerging as an important drug transporter because of its expression in both the liver and kidney, two major eliminating organs, and its ability to transport not only a wide variety of xenobiotics but also numerous physiologically important endogenous compounds, like creatinine and cGMP. However, OAT2 has received relatively little attention compared with other OATs and solute carriers (SLCs), like organic cation transporters, sodium-dependent taurocholate cotransporting polypeptide, multidrug and toxin extrusion proteins, and organic anion-transporting polypeptides. Overall, the literature describing OAT2 is rapidly evolving, with numerous publications contradicting each other regarding the transport mechanism, tissue distribution, and transport of creatinine and cGMP, two important endogenous OAT2 substrates. Despite its status as a liver and kidney SLC, tools for assessing its activity and inhibition are lacking, and its role in drug disposition and elimination remains to be defined. The current review focuses on the available and emerging literature describing OAT2. We envision that OAT2 will gain more prominence as its expression, substrate, and inhibitor profile is investigated further and compared with other SLCs.

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Interaction of human organic anion transporter 2 (OAT2) and sodium taurocholate cotransporting polypeptide (NTCP) with antineoplastic drugs

Cited by 30 publications

References 39 publications

The role of OAT2 (SLC22A7) in the cyclic nucleotide biokinetics of human erythrocytes

The role of OAT2 (SLC22A7) in the cyclic nucleotide biokinetics of human erythrocytes

Liver Receptor Homolog-1 Regulates Organic Anion Transporter 2 and Docetaxel Pharmacokinetics

Organic Anion Transporter 2: An Enigmatic Human Solute Carrier

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