Functional characterization of the basolateral rat liver organic anion transporting polypeptide

Kullak-Ublick, Gerd-Achim; Hagenbuch, Bruno; Stieger, Bruno; Wolkoff, Allan W.; Meier, Peter J.

doi:10.1002/hep.1840200222

Cited by 71 publications

(78 citation statements)

References 25 publications

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“…21 In fact, PB as well as 3-MC tended to decrease Oatp1 protein expression. This is surprising because PB treatment enhances the plasma disappearance of bromosulfophthalein, 1 which is a substrate of Oatp1, 5,11,15,18 but not of Oatp2. 15 These results suggest that Oatp1 is not solely responsible for hepatic bromosulfophtalein uptake.…”

Section: Discussionmentioning

confidence: 99%

“…7,9,11 Based on the spectrum of substrates transported by these proteins, chemical-induced up-regulation of organic anion transporting proteins may be the mechanism by which pretreatment of rats with PB and PCN resulted in enhanced hepatic transport of cardiac glycosides in previous studies. [1][2][3][4] A limited number of studies have examined the effects of various chemicals on the expression of Oatp1 and Oatp2.…”

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confidence: 99%

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Differential Effects of Microsomal Enzyme-Inducing Chemicals on the Hepatic Expression of Rat Organic Anion Transporters, Oatp1 and Oatp2

Rausch‐Derra

2001

Hepatology

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The organic anion transporting polypeptides, Oatp1 (Slc21a1) and Oatp2 (Slc21a5), mediate hepatic uptake of cardiac glycosides. Previously, we demonstrated that chemicals that increase cytochrome P450s differentially affect hepatic uptake of cardiac glycosides. We postulated that increased uptake of cardiac glycosides observed after pretreatment of animals with phenobarbital (PB) and pregnenolone-16␣-carbonitrile ( Hepatic clearance and biliary excretion of drugs and their metabolites can occur through passive transport or through active transport (carrier-mediated) systems. Previous studies from this laboratory described a phenomenon in which pretreatment of animals with chemicals known to differentially increase specific microsomal cytochrome P450 enzymes also enhanced both hepatic plasma clearance and biliary excretion of a number of choleophiles, including cardiac glycosides. [1][2][3][4] Specifically, pretreatment of rats with two compounds known classically to activate CYP2B and CYP3A transcription, the barbiturate phenobarbital (PB) and the synthetic steroid pregenenolone-16␣-carbonitrile (PCN), respectively, resulted in the decreased plasma half-life, increased hepatic clearance, and decreased toxicity of cardiac glycosides. In contrast, pretreatment of rats with chemicals known to act through the aryl hydrocarbon receptor resulted in a slight suppression of cardiac glycoside plasma clearance by the liver. 2 Further studies demonstrated that PCN increased the maximal velocity and affinity of ouabain uptake into hepatocytes, 3 suggesting that this chemical altered the hepatocellular capacity and affinity for choleophilic substrates. In subsequent studies, an energydependent, Na ϩ -independent carrier-mediated transport system for ouabain was identified. This Na ϩ -independent transport system was sensitive to inhibition by neutral (e.g., digoxin), acidic (e.g., taurocholate), and basic (e.g., quinine) compounds. 4 Together, these findings suggested that a multispecific, Na ϩ -independent hepatic transport system existed, which could be positively modulated by microsomal enzymeinducing chemicals, specifically PB and PCN.Since these earlier reports, 1-4 specific mediators of this hepatic Na ϩ -independent transport system have been cloned and characterized, and consist of several members of the rat organic anion transporting polypeptide (Oatp) family. The primary forms expressed in rat liver include, Oatp1 (gene symbol: Slc21a1), Oatp2 (Slc21a5), and liver-specific transporter 1 (rlst-1) or Oatp4 (Slc21a10). In rat liver, the organic anion transporting polypeptides, Oatp1, 5 Oatp2, 6,7 and rlst-1/ Oatp4, 8-10 transport a number of conjugated and unconjugated xenobiotics and endobiotics in a charge-independent manner. The substrates for this family of transporters include: the cardiac glycosides, the statin class of lipid-lowering drugs, human immunodeficiency virus-protease inhibitors, bile acids, eicosanoids, thyroid hormone and thyroid hormone conjugates, steroid hormone conjugates, and numerous peptidede...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Differential Effects of Microsomal Enzyme-Inducing Chemicals on the Hepatic Expression of Rat Organic Anion Transporters, Oatp1 and Oatp2

Rausch‐Derra

2001

Hepatology

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“…Several transport proteins that may be involved in this transport include the organic anion transporting polypeptides, OATP1, OATP2, and OATP4 (Cattori et al, 2001;Jacquemin et al, 1994;Kullak-Ublick et al, 1994), the organic cation transporter, OCT1 (Grundemann et al, 1994), the metal transport protein, MTP1 (Abboud and Haile, 2000) and amino acid or peptide transporters that are localized in the sinusoidal plasma membrane. Although these carriers have not been implicated in the transport of metals out of hepatocytes, most of them are multispecific transporters and may be able to carry metal ions or conjugated forms of metals.…”

Section: Mimicry and The Hepatic Transport Of CD 2+mentioning

confidence: 99%

Molecular and ionic mimicry and the transport of toxic metals

Bridges

Zalups

2005

Toxicology and Applied Pharmacology

676

460

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Despite many scientific advances, human exposure to, and intoxication by, toxic metal species continues to occur. Surprisingly, little is understood about the mechanisms by which certain metals and metal-containing species gain entry into target cells. Since there do not appear to be transporters designed specifically for the entry of most toxic metal species into mammalian cells, it has been postulated that some of these metals gain entry into target cells, through the mechanisms of ionic and/or molecular mimicry, at the site of transporters of essential elements and/or molecules. The primary purpose of this review is to discuss the transport of selective toxic metals in target organs and provide evidence supporting a role of ionic and/or molecular mimicry. In the context of this review, molecular mimicry refers to the ability of a metal ion to bond to an endogenous organic molecule to form an organic metal species that acts as a functional or structural mimic of essential molecules at the sites of transporters of those molecules. Ionic mimicry refers to the ability of a cationic form of a toxic metal to mimic an essential element or cationic species of an element at the site of a transporter of that element. Molecular and ionic mimics can also be sub-classified as structural or functional mimics. This review will present the established and putative roles of molecular and ionic mimicry in the transport of mercury, cadmium, lead, arsenic, selenium, and selected oxyanions in target organs and tissues.

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“…In vitro synthesis of Ntcp-, Oatp1-, and Oatp2-cRNA was performed as described. 11,18,19 X. laevis oocytes were prepared 20 and cultured overnight at 18°C. Healthy oocytes were microinjected with 0.5 ng of Ntcp-, 1 ng of Oatp1-, or 5 ng of Oatp2-cRNA and cultured for 2 (Ntcp) or 3 (Oatp1, Oatp2) days in a medium containing 88 mmol/L NaCl, 2.4 mmol/L NaHCO 3 , 1 mmol/L KCl, 0.3 mmol/L Ca(NO 3 ), 0.41 mmol/L CaCl 2 , 0.82 mmol/L MgSO 4 , 0.05 mg/mL gentamicin, and 15 mmol/L HEPES (pH 7.6).…”

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confidence: 99%

Rifamycin SV and rifampicin exhibit differential inhibition of the hepatic rat organic anion transporting polypeptides, Oatp1 and Oatp2

et al. 2000

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The antibiotics, rifamycin SV and rifampicin, are known to interfere with hepatic bile salt and organic anion uptake. The aim of this study was to explore which transport systems are affected. In short-term-cultured rat hepatocytes, low concentrations (10 mol/L) of both compounds inhibited mainly sodium-independent taurocholate uptake, whereas higher concentrations (100 mol/L) also inhibited sodium-dependent taurocholate uptake. In Xenopus laevis oocytes expressing the Na ؉ /taurocholate cotransporting polypeptide (Ntcp), high rifamycin SV and rifampicin concentrations were required for inhibition of taurocholate uptake. In contrast, sodiumindependent taurocholate uptake mediated by the organic anion transporting polypeptides, Oatp1 and Oatp2, was already substantially inhibited by 10 mol/L rifamycin SV. Rifampicin potently inhibited Oatp2-mediated taurocholate uptake, but did not interfere with Oatp1-mediated taurocholate uptake. Similar effects of rifamycin SV and rifampicin were found for Oatp1-and Oatp2-mediated estradiol-17␤-glucuronide transport. Dixon plot analysis yielded a pattern compatible with competitive inhibition of estradiol-17␤-glucuronide transport with K i estimates of 6.6 mol/L and 7.3 mol/L for rifamycin SV-induced inhibition of Oatp1 and Oatp2, respectively, and of 1.4 mol/L for rifampicin-induced inhibition of Oatp2. These results demonstrate that rifamycin SV and rifampicin exhibit differential inhibition on Oatp1 and Oatp2, and identify rifampicin as a selective Oatp2 inhibitor. The data indicate that these inhibitors can be used to determine the in vivo relevance of Oatp1 and Oatp2 for the overall bioavailability and disposition of drugs and other Oatp1/2 substrates. (HEPATOLOGY 2000;32:82-86.)The antibiotics, rifamycin SV and rifampicin, are mainly eliminated by hepatic uptake, metabolism, and excretion into bile. 1,2 For rifamycin SV, hepatic first-pass elimination is so efficient that oral administration is unfeasible. 3 Rifamycin SV interferes with the hepatic elimination of many compounds including bilirubin, bromosulfophtalein, and indocyanine green. 4,5 Rifampicin has been shown to increase serum bile salt concentrations in 72% of patients 6 after the first dose, suggesting acute inhibition of hepatocellular bile salt uptake. 7 In isolated rat hepatocytes, rifamycin SV and rifampicin inhibited cholate uptake, with K i values of 30 and 46 µmol/L in the absence and of 18 and 31 µmol/L in the presence of bovine serum albumin (3%). 8 The corresponding K i values for taurocholate were 60 and 122 µmol/L in the absence and 128 and 237 µmol/L in the presence of bovine serum albumin. 8 The values reported for cholate are close to the serum concentrations of 5 to 10 µmol/L measured after administration of therapeutic doses of rifamycin SV or rifampicin in humans. 1,9 Recently, several carrier proteins involved in the hepatic uptake of bile salts and other albumin-bound organic anions have been cloned from rat liver. 10 The Na ϩ /taurocholate cotransporting polypeptide, Ntcp, mediates sodiu...

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Functional characterization of the basolateral rat liver organic anion transporting polypeptide

Cited by 71 publications

References 25 publications

Differential Effects of Microsomal Enzyme-Inducing Chemicals on the Hepatic Expression of Rat Organic Anion Transporters, Oatp1 and Oatp2

Differential Effects of Microsomal Enzyme-Inducing Chemicals on the Hepatic Expression of Rat Organic Anion Transporters, Oatp1 and Oatp2

Molecular and ionic mimicry and the transport of toxic metals

Rifamycin SV and rifampicin exhibit differential inhibition of the hepatic rat organic anion transporting polypeptides, Oatp1 and Oatp2

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