Localization and function of the organic anion–transporting polypeptide Oatp2 in rat liver

Reichel, Christoph; Gao, Bo; Montfoort, Jessica van; Cattori, Valentino; Rahner, Christoph; Hagenbuch, Bruno; Stieger, Bruno; Kamisako, Toshinori; Meier, Peter J.

doi:10.1016/s0016-5085(99)70463-4

Cited by 190 publications

(184 citation statements)

References 28 publications

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“…Our bilirubin data are in line with in vitro studies demonstrating that Oatp1a1 (27), OATP1B1, and OATP1B3 (28,29) can transport bilirubin glucuronides with high affinity (K m values < 0.5 μM). Furthermore, in humans the SLCO1B1*1b (Val174Ala), -*5 (Asp130Asn), and -*15 (Asp130Asn + Val174Ala) haplotypes have also been associated with significantly (albeit modestly) increased plasma levels of both conjugated bilirubin and UCB (30)(31)(32)(33).…”

Section: Figuresupporting

confidence: 89%

Organic anion transporting polypeptide 1a/1b–knockout mice provide insights into hepatic handling of bilirubin, bile acids, and drugs

Steeg

Wagenaar²,

Kruijssen³

et al. 2010

J. Clin. Invest.

193

196

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Organic anion transporting polypeptides (OATPs) are uptake transporters for a broad range of endogenous compounds and xenobiotics. To investigate the physiologic and pharmacologic roles of OATPs of the 1A and 1B subfamilies, we generated mice lacking all established and predicted mouse Oatp1a/1b transporters (referred to as Slco1a/1b -/-mice, as SLCO genes encode OATPs). Slco1a/1b -/-mice were viable and fertile but exhibited markedly increased plasma levels of bilirubin conjugated to glucuronide and increased plasma levels of unconjugated bile acids. The unexpected conjugated hyperbilirubinemia indicates that Oatp1a/ 1b transporters normally mediate extensive hepatic reuptake of glucuronidated bilirubin. We therefore hypothesized that substantial sinusoidal secretion and subsequent Oatp1a/1b-mediated reuptake of glucuronidated compounds can occur in hepatocytes under physiologic conditions. This alters our perspective on normal liver functioning. Slco1a/1b -/-mice also showed drastically decreased hepatic uptake and consequently increased systemic exposure following i.v. or oral administration of the OATP substrate drugs methotrexate and fexofenadine. Importantly, intestinal absorption of oral methotrexate or fexofenadine was not affected in Slco1a/1b -/-mice. Further analysis showed that rifampicin was an effective and specific Oatp1a/1b inhibitor in controlling methotrexate pharmacokinetics. These data indicate that Oatp1a/1b transporters play an essential role in hepatic reuptake of conjugated bilirubin and uptake of unconjugated bile acids and drugs. Slco1a/1b -/-mice will provide excellent tools to study further the role of Oatp1a/1b transporters in physiology and drug disposition.

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Section: Figuresupporting

confidence: 89%

Organic anion transporting polypeptide 1a/1b–knockout mice provide insights into hepatic handling of bilirubin, bile acids, and drugs

Steeg

Wagenaar²,

Kruijssen³

et al. 2010

J. Clin. Invest.

193

196

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“…Rat Oatp1a4 and human OATP1B1 and OATP1B3 (table 1) transport unconjugated or conjugated bilirubin (Briz et al, 2003;Cui et al, 2001b;Konig et al, 2000;Reichel et al, 1999). Corroboratively, recent pharmacogenetic studies have linked polymorphisms in the SLCO1B1 and SLCO1B3 genes with unconjugated and conjugated plasma bilirubin levels (Johnson et al, 2009;Sanna et al, 2009;Zhang et al, 2007).…”

Section: Bilirubinmentioning

confidence: 99%

The emerging role of transport systems in liver function tests

Stieger

Heger

Graaf

et al. 2012

European Journal of Pharmacology

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Liver function tests are of critical importance for the management of patients with severe or terminal liver disease. They are also used as prognostic tools for planning liver resections. In recent years many transport systems have been identified that also transport substances employed in liver function tests. Such substances include endogenous bilirubin or exogenously administered indocyanine green, agents for magnetic resonance imaging, agents for single photon emission computed tomography or agents for breath tests. The increasing functional and molecular information on the respective transport systems should improve the management and as a result the outcome of patients scheduled for liver surgery or transplantation. To achieve the latter goal, clinical studies that assess individual patients' liver function over the course of their disease with liver function tests are needed to firmly establish and validate recently introduced and novel liver function markers. The emerging role of transport systems in liver function tests Bruno Stieger is supported by grant # 31003A_124652 from the Swiss National Science foundation. AbstractLiver function tests are of critical importance for the management of patients with severe or terminal liver disease. They are also used as prognostic tools for planning liver resections. In recent years many transport systems have been identified, that also transport substances employed in liver function tests. Such substances include endogenous bilirubin or exogenously administered indocyanine green, agents for magnetic resonance imaging, agents for single photon emission computed tomography or agents for breath tests. The increasing functional and molecular information on the respective transport systems should improve the management and as a result the outcome of patients scheduled for liver surgery or transplantation. To achieve the latter goal, clinical studies that assess individual patients liver function over the course of their disease with liver function testes are needed to firmly establish and validate recently introduced and novel liver function markers.

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“…Rabbit polyclonal antibodies against rat Oatp1 (Slc21a1), 16,17 rat Oatp2 (Slc21a5), 18 rat Oatp4 (Slc21a10), 19 and rat Mrp2 (Abcc2) 20 were used. Sodium dodecyl sulfate …”

Section: Expression Of Oatps and Mrp2 In Hepatocytesmentioning

confidence: 99%

Gd-BOPTA Transport Into Rat Hepatocytes: Pharmacokinetic Analysis of Dynamic Magnetic Resonance Images Using a Hollow-Fiber Bioreactor

Planchamp

Gex‐Fabry²,

Dornier³

et al. 2004

Investigative Radiology

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Rationale and Objectives:To investigate the transport of the hepatobiliary magnetic resonance (MR) imaging contrast agent Gd-BOPTA into rat hepatocytes. Materials and Methods:In a MR-compatible hollow-fiber bioreactor containing hepatocytes, MR signal intensity was measured over time during the perfusion of Gd-BOPTA. For comparison, the perfusion of an extracellular contrast agent (Gd-DTPA) was also studied. A compartmental pharmacokinetic model was developed to describe dynamic signal intensity-time curves. Results: The dynamic signal intensity-time curves of the hepatocyte hollow-fiber bioreactor during Gd-BOPTA perfusion were adequately fitted by 2 compartmental models. Modeling permitted to discriminate between the behaviors of the extracellular contrast agent (Gd-DTPA) and the hepatobiliary contrast agent (Gd-BOPTA). It allowed the successfully quantification of the parameters involved in such differences. Gd-BOPTA uptake was saturable at high substrate concentrations. Conclusions: The transport of Gd-BOPTA into rat hepatocytes was successfully described by compartmental analysis of the signal intensity recorded over time and supported the hypothesis of a transporter-mediated uptake.

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Localization and function of the organic anion–transporting polypeptide Oatp2 in rat liver

Cited by 190 publications

References 28 publications

Organic anion transporting polypeptide 1a/1b–knockout mice provide insights into hepatic handling of bilirubin, bile acids, and drugs

Organic anion transporting polypeptide 1a/1b–knockout mice provide insights into hepatic handling of bilirubin, bile acids, and drugs

The emerging role of transport systems in liver function tests

Gd-BOPTA Transport Into Rat Hepatocytes: Pharmacokinetic Analysis of Dynamic Magnetic Resonance Images Using a Hollow-Fiber Bioreactor

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