Hepatocellular Organic Anion–Transporting Polypeptides (OATPs) and Multidrug Resistance–Associated Protein 2 (MRP2) Are Inhibited by Silibinin

Wlcek, Katrin; Koller, Fabienne; Ferenci, Péter; Stieger, Bruno

doi:10.1124/dmd.113.051037

Cited by 31 publications

(38 citation statements)

References 61 publications

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“…Nevertheless, available data suggest several consistent disease associations, particularly for SLCO1B3 and SLCO2B1, in PCa. Whether or not cancer-associated expression of transporters will be feasible targets for inhibition remains a significant question, given the critical function these proteins play in normal clearance of endogenous metabolites and in excretion of drugs and toxins (74,75). However, tumoral expression of transporters may still serve as relevant biomarkers for cancers with efficient steroid uptake for which more aggressive targeting of the androgen axis may be warranted.…”

Section: Resultsmentioning

confidence: 99%

Minireview: SLCO and ABC Transporters: A Role for Steroid Transport in Prostate Cancer Progression

2014

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Androgens play a critical role in the development and progression of prostate cancer (PCa), and androgen deprivation therapy via surgical or medical castration is front-line therapy for patients with advanced PCa. However, intratumoral testosterone levels are elevated in metastases from patients with castration-resistant disease, and residual intratumoral androgens have been implicated in mediating ligand-dependent mechanisms of androgen receptor activation. The source of residual tissue androgens present despite castration has not been fully elucidated, but proposed mechanisms include uptake and conversion of adrenal androgens, such as dehdroepiandrosterone to testosterone and dihydrotestosterone, or de novo androgen synthesis from cholesterol or progesterone precursors. In this minireview, we discuss the emerging evidence that suggests a role for specific transporters in mediating transport of steroids into or out of prostate cells, thereby influencing intratumoral androgen levels and PCa development and progression. We focus on the solute carrier and ATP binding cassette gene families, which have the most published data for a role in PCa-related steroid transport, and review the potential impact of genetic variation on steroid transport activity and PCa outcomes. Continued assessment of transport activity in PCa models and human tumor tissue is needed to better delineate the different roles these transporters play in physiologic and neoplastic settings, and in order to determine whether targeting the uptake of steroid substrates by specific transporters may be a clinically feasible therapeutic strategy. (Endocrinology 155: 4124 -4132, 2014)

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Section: Resultsmentioning

confidence: 99%

Minireview: SLCO and ABC Transporters: A Role for Steroid Transport in Prostate Cancer Progression

2014

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“…It was shown in 2006 that silibinin inhibits hOATP1B3-mediated uptake of amanitin into hOATP1B3-expressing MDCKII cells (Letschert, Faulstich, Keller, & Keppler, 2006). Two recent studies further characterized the interactions of silymarin and some of its major constituents with respect to inhibition of OATP-mediated uptake (Kock, Xie, Hawke, Oberlies, & Brouwer, 2013; Wlcek, Koller, Ferenci, & Stieger, 2013). In these studies silbinin inhibited OATP-mediated substrate uptake.…”

Section: Transport Of Natural Products By Oatpsmentioning

confidence: 99%

Organic Anion-Transporting Polypeptides

Stieger

Hagenbuch

2014

Current Topics in Membranes

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142

106

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Organic anion transporting polypeptides or OATPs are central transporters in the disposition of drugs and other xenobiotics. In addition, they mediate transport of a wide variety of endogenous substrates. The critical role of OATPs in drug disposition has spurred research both in academia and in the pharmaceutical industry. Translational aspects with clinical questions are the focus in academia, while the pharmaceutical industry tries to define and understand the role these transporters play in pharmacotherapy. The present overview summarizes our knowledge on the interaction of food constituents with OATPs, and on the OATP transport mechanisms. Further, it gives an update on the available information on the structure-function relationship of the OATPs, and finally, covers the transcriptional and posttranscriptional regulation of OATPs.

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“…The incidence of drug-induced hyperbilirubinemia has been documented since rifamycin SV or cyclosporin A was reported to increase the plasma levels of total bilirubins without an elevation of liver enzyme, such as ALT and AST, in humans (Acocella et al, 1965;List et al, 1993). Recently, many researchers have focused on the mechanism of drug-induced hyperbilirubinemia (Zucker et al, 2001;Campbell et al, 2004;Chang et al, 2013;Wlcek et al, 2013;Chiou et al, 2014); however, the exact mechanism of drug-induced hyperbilirubinemia in humans and the relationship between the biomarkers and DDI from a quantitative perspective have not been elucidated. In other cases, previous studies have shown that when the renal transporters were inhibited by drugs, the plasma concentrations of creatinine, N-methylnicotinamide, and 6b-hydroxycortisol increased with the inhibition of OCT2 and/or MATEs, MATEs, and OAT3 by drugs, respectively (Imamura et al, 2011(Imamura et al, , 2014Ito et al, 2012).…”

Section: Biomarkers For Inhibition Of Transportersmentioning

confidence: 99%

Utility of Bilirubins and Bile Acids as Endogenous Biomarkers for the Inhibition of Hepatic Transporters

Watanabe¹,

Miyake²,

Shimizu³

et al. 2015

Drug Metab Dispos

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It is useful to identify endogenous substrates for the evaluation of drug-drug interactions via transporters. In this study, we investigated the utility of bilirubins, substrates of OATPs and MRP2, and bile acids and substrates of NTCP and BSEP, as biomarkers for the inhibition of transporters. In rats administered 20 and 80 mg/kg rifampicin, the plasma levels of bilirubin glucuronides were elevated, gradually decreased, and almost returned to the baseline level at 24 hours after administration without an elevation of alanine aminotransferase (ALT) and aspartate aminotransferase (AST). This result indicates the transient inhibition of rOatps and/or rMrp2. Although the correlation between free plasma concentrations and IC 50 values of rOatps depended on the substrates used in the in vitro studies, the inhibition of rOatps by rifampicin was confirmed in the in vivo study using valsartan as a substrate of rOatps. In rats administered 10 and 30 mg/kg cyclosporin A, the plasma levels of bile acids were elevated and persisted for up to 24 hours after administration without an elevation of ALT and AST. This result indicates the continuous inhibition of rNtcp and/or rBsep, although there were differences between the free plasma or liver concentrations and IC 50 values of rNtcp or rBsep, respectively. This study suggests that the monitoring of bilirubins and bile acids in plasma is useful in evaluating the inhibitory potential of their corresponding transporters.

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Hepatocellular Organic Anion–Transporting Polypeptides (OATPs) and Multidrug Resistance–Associated Protein 2 (MRP2) Are Inhibited by Silibinin

Cited by 31 publications

References 61 publications

Minireview: SLCO and ABC Transporters: A Role for Steroid Transport in Prostate Cancer Progression

Minireview: SLCO and ABC Transporters: A Role for Steroid Transport in Prostate Cancer Progression

Organic Anion-Transporting Polypeptides

Utility of Bilirubins and Bile Acids as Endogenous Biomarkers for the Inhibition of Hepatic Transporters

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