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Fukumura, Satoko; Takikawa, Hajime; Yamanaka, Masami

doi:10.1023/a:1011900820409

Cited by 25 publications

(1 citation statement)

References 23 publications

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“…This clearance occurs by uptake on the sinusoidal or basolateral side of the liver cell followed by biliary excretion across the canilicular membrane. Rat oatp1 has been localized to the basolateral surface of the hepatocyte (34), consistent with a role in hepatic pravastatin clearance (35), whereas the unrelated multi-drug resistance protein, cMOAT (canilicular multi-specific organic anion transporter), is thought to be the canilicular transporter (36). With regard to renal elimination of this drug, there is uptake from the basolateral side of the renal tubular epithelial cell in addition to glomerular filtration (37).…”

Section: Fig 3 Nucleotide and Amino Acid Sequence Of Human Oatp2mentioning

confidence: 95%

A Novel Human Hepatic Organic Anion Transporting Polypeptide (OATP2)

Hsiang¹,

Zhu²,

Wang³

et al. 1999

Journal of Biological Chemistry

581

105

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A novel human organic transporter, OATP2, has been identified that transports taurocholic acid, the adrenal androgen dehydroepiandrosterone sulfate, and thyroid hormone, as well as the hydroxymethylglutaryl-CoA reductase inhibitor, pravastatin. OATP2 is expressed exclusively in liver in contrast to all other known transporter subtypes that are found in both hepatic and nonhepatic tissues. OATP2 is considerably diverged from other family members, sharing only 42% sequence identity with the four other subtypes. Furthermore, unlike other subtypes, OATP2 did not transport digoxin or aldosterone. The rat isoform oatp1 was also shown to transport pravastatin, whereas other members of the OATP family, i.e. rat oatp2, human OATP, and the prostaglandin transporter, did not. Cis-inhibition studies indicate that both OATP2 and roatp1 also transport other statins including lovastatin, simvastatin, and atorvastatin. In summary, OATP2 is a novel organic anion transport protein that has overlapping but not identical substrate specificities with each of the other subtypes and, with its liver-specific expression, represents a functionally distinct OATP isoform. Furthermore, the identification of oatp1 and OATP2 as pravastatin transporters suggests that they are responsible for the hepatic uptake of this liver-specific hydroxymethylglutaryl-CoA reductase inhibitor in rat and man.

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Section: Fig 3 Nucleotide and Amino Acid Sequence Of Human Oatp2mentioning

confidence: 95%

A Novel Human Hepatic Organic Anion Transporting Polypeptide (OATP2)

Hsiang¹,

Zhu²,

Wang³

et al. 1999

Journal of Biological Chemistry

581

105

View full text Add to dashboard Cite

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Genipin enhances Mrp2 (Abcc2)-mediated bile formation and organic anion transport in rat liver

et al. 2004

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Inchin-ko-to (ICKT), an herbal medicine, and its ingredients exert potent choleretic effects by a "bile acid-independent" mechanism. The current study was designed to determine whether ICKT or its ingredients potentiate multidrug resistance-associated protein 2 (Mrp2; Abcc2)-mediated choleresis in vivo. Biliary secretion of Mrp2 substrates and the protein mass, subcellular localization, and messenger RNA (mRNA) level of Mrp2 were assessed in rat liver after infusion of genipin, an intestinal bacterial metabolite of geniposide, a major ingredient of ICKT. The function of Mrp2 was also assessed by the adenosine triphosphate (ATP)-dependent uptake of Mrp2-specific substrates using canalicular membrane vesicles (CMVs) from the liver. Infusion of genipin increased bile flow by 230%. It also increased biliary secretion of bilirubin conjugates and reduced glutathione (GSH) by 513% and 336%, respectively, but did not increase bile acid secretion. The ATP-dependent uptake of estradiol 17-␤-D-glucuronide (E 2 17␤G; by 265%), leukotriene C4 (LTC 4 ; by 161%), taurolithocholate-3-sulfate (TLC-3S; by 266%), and methotrexate (MTX; by 234%) was significantly stimulated in the CMVs from the liver. These effects were not observed in Mrp2-deficient rats. Under these conditions, genipin treatment increased the protein mass of Mrp2 in the CMVs but not the mRNA level. In immunoelectron microscopic studies, a marked increase in Mrp2 density in the canalicular membrane (CM) and microvilli was observed in the genipin-treated liver tissue sections when compared with the vehicle-treated liver tissue sections. In conclusion, genipin may enhance the bile acid-independent secretory capacity of hepatocytes, mainly by stimulation of exocytosis and insertion of Mrp2 in the bile canaliculi. ICKT may be a potent therapeutic agent for a number of cholestatic liver diseases. (HEPATOLOGY 2004;39:167-178.)

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Comparison of urinary excretion of pravastatin and temocapril in bile duct-ligated rats and Eisai hyperbilirubinemic rats (EHBR)

Takada

Tachizawa

Kurihara

et al. 2004

Journal of Hepato-Biliary-Pancreatic Surgery

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The absence of biliary excretion of anionic drugs was compensated for by urinary excretion in BDLR and EHBR, and the compensation was more efficient with pravastatin than with temocapril. In patients with complete bile duct obstruction, the only pathway for the elimination of cholephilic compounds is through the urine. Although changes in various transporters in the liver and kidney in cholestasis have been elucidated, little is known about how effectively the elimination of these compounds is compensated for by urinary excretion.

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Abstract: These findings further support the multiplicity of canalicular organic anion transport, and pravastatin is considered to be excreted through a canalicular transporter which is absent in EHBR in addition to through cMOAT.

Cited by 25 publications

References 23 publications

A Novel Human Hepatic Organic Anion Transporting Polypeptide (OATP2)

A Novel Human Hepatic Organic Anion Transporting Polypeptide (OATP2)

Genipin enhances Mrp2 (Abcc2)-mediated bile formation and organic anion transport in rat liver

Comparison of urinary excretion of pravastatin and temocapril in bile duct-ligated rats and Eisai hyperbilirubinemic rats (EHBR)

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