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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Functional Characterization of Rat Organic Anion Transporter 2 in LLC-PK1 Cells

Naomi Morita, Hiroyuki Kusuhara, Takashi Sekine, Hitoshi Endou and Yuichi Sugiyama
Journal of Pharmacology and Experimental Therapeutics September 2001, 298 (3) 1179-1184;
Naomi Morita
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Hiroyuki Kusuhara
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Takashi Sekine
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Hitoshi Endou
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Yuichi Sugiyama
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Abstract

Rat organic anion transporter 2 (rOat2) is abundantly expressed in the liver and localized to the basolateral membrane. A previous study using the Xenopus laevis oocyte expression system has shown that rOat2 transports organic anions such as salicylate (Sekine et al., 1998) and, in the present study, rOat2 was characterized using a mammalian expression system. In addition to the substrates previously shown to be transported by rOat2, three substrates, indomethacin [IDM, Michaelis-Menten constant (Km) of 0.37 μM] and nucleoside derivatives such as 3′-azido-3′-deoxythymidine (AZT,Km of 26 μM) and 2′,3′-dideoxycytidine (ddC, Km of 3.08 mM), were also identified for the first time The rank order of rOat2-mediated transport of these substrates was IDM > salicylate > prostaglandin E2 > AZT > ddC >p-aminohippurate (PAH). Ketoprofen, indocyanine green and glibenclamide are potent inhibitors of the uptake of [14C]salicylate via rOat2 (Kiof ∼12 μM), while diclofenac, benzoate, verapamil, ibuprofen, and tolbutamide are moderate inhibitors (Ki of ∼150 μM). The affinity of PAH, a common substrate for the OAT family, for rOat2 is low (Ki > 1 mM) compared with the other members of the OAT family (rOat1 and rOat3). Salicylate and IDM are also substrates for rOat1, but their affinity for rOat2 was higher than that for rOat1. The present study shows that rOat2 is a multispecific transporter and suggests that it may be involved at least partly, in the hepatic uptake of IDM, salicylate and nucleoside derivatives.

Footnotes

  • This work was supported by CREST (Core Research for Evolutional Science and Technology) of Japan Science and Technology Corporation.

  • Abbreviations:
    OATP
    organic anion-transporting polypeptide
    OAT
    organic anion transporter
    PAH
    p-aminohippurate
    NSAID
    nonsteroidal anti-inflammatory drug
    MTX
    methotrexate
    IDM
    indomethacin
    α-KG
    α-ketoglutarate
    ddC
    2′,3′-dideoxycytidine
    AZT
    3′-azido-3′-deoxythymidine
    TBS-T
    Tris-buffered saline containing 0.05% Tween 20
    PGE2
    prostaglandin E2
    • Received January 30, 2001.
    • Accepted May 28, 2001.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 298 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 298, Issue 3
1 Sep 2001
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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Functional Characterization of Rat Organic Anion Transporter 2 in LLC-PK1 Cells

Naomi Morita, Hiroyuki Kusuhara, Takashi Sekine, Hitoshi Endou and Yuichi Sugiyama
Journal of Pharmacology and Experimental Therapeutics September 1, 2001, 298 (3) 1179-1184;

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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Functional Characterization of Rat Organic Anion Transporter 2 in LLC-PK1 Cells

Naomi Morita, Hiroyuki Kusuhara, Takashi Sekine, Hitoshi Endou and Yuichi Sugiyama
Journal of Pharmacology and Experimental Therapeutics September 1, 2001, 298 (3) 1179-1184;
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