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Research ArticleCELLULAR AND MOLECULAR

Human Liver-Specific Organic Anion Transporter, LST-1, Mediates Uptake of Pravastatin by Human Hepatocytes

Daisuke Nakai, Rie Nakagomi, Yoshitake Furuta, Taro Tokui, Takaaki Abe, Toshihiko Ikeda and Kenji Nishimura
Journal of Pharmacology and Experimental Therapeutics June 2001, 297 (3) 861-867;
Daisuke Nakai
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Rie Nakagomi
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Yoshitake Furuta
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Taro Tokui
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Takaaki Abe
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Toshihiko Ikeda
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Kenji Nishimura
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Abstract

Involvement of LST-1 (a human liver-specific transporter, also called OATP2) as the major transporter in the uptake of pravastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, by human liver was demonstrated. The hepatic uptake of pravastatin evaluated using human hepatocytes was Na+-independent and reached saturation with a Michaelis constant (Km) of 11.5 ± 2.2 μM. The uptake of pravastatin was temperature-dependent and was inhibited by estradiol-17β-d-glucuronide, taurocholic acid, bromosulfophthalein, and simvastatin acid, but not byp-aminohippurate. Estradiol-17β-d-glucuronide competitively inhibited pravastatin uptake with an inhibition constant comparable to theKm value for estradiol-17β-d-glucuronide transport, indicating that a common transporter mediates the transport of pravastatin and estradiol-17β-d-glucuronide in human hepatocytes. The results obtained with human hepatocytes agreed with those obtained with LST-1 expressing Xenopus oocytes. Oocytes microinjected with human liver polyadenylated mRNA showed Na+-independent uptake of pravastatin and estradiol-17β-d-glucuronide. A simultaneous injection of LST-1 antisense oligonucleotides completely abolished this uptake. Expression of LST-1 was immunohistochemically demonstrated in the human hepatocytes, but not in Hep G2 cells, which showed very low uptake of pravastatin. Therefore, LST-1 was regarded as a key molecule for pravastatin in liver-specific inhibition of cholesterol synthesis, making pravastatin accessible to the target enzyme, which would otherwise not be inhibited by this hydrophilic drug.

Footnotes

  • Send reprint requests to: Dr. Taro Tokui, Drug Metabolism and Pharmacokinetics Research Laboratories, Sankyo Co., Ltd., 2-58 Hiromachi, Shinagawa-ku, Tokyo, 140-8710, Japan. E-mail:tokuit{at}shina.sankyo.co.jp

  • Abbreviations:
    HMG-CoA
    3-hydroxy-3-methylglutaryl coenzyme A
    OATP2
    organic anion transporting polypeptide 2
    LST-1
    human liver-specific organic anion transporter
    KHL
    keyhole limpet hemocyanin
    Km
    Michaelis constant
    Vmax
    maximum uptake rate
    Pdif
    nonspecific uptake clearance
    Ki
    inhibition constant
    • Received October 19, 2000.
    • Accepted January 2, 2001.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 297 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 297, Issue 3
1 Jun 2001
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Research ArticleCELLULAR AND MOLECULAR

Human Liver-Specific Organic Anion Transporter, LST-1, Mediates Uptake of Pravastatin by Human Hepatocytes

Daisuke Nakai, Rie Nakagomi, Yoshitake Furuta, Taro Tokui, Takaaki Abe, Toshihiko Ikeda and Kenji Nishimura
Journal of Pharmacology and Experimental Therapeutics June 1, 2001, 297 (3) 861-867;

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Research ArticleCELLULAR AND MOLECULAR

Human Liver-Specific Organic Anion Transporter, LST-1, Mediates Uptake of Pravastatin by Human Hepatocytes

Daisuke Nakai, Rie Nakagomi, Yoshitake Furuta, Taro Tokui, Takaaki Abe, Toshihiko Ikeda and Kenji Nishimura
Journal of Pharmacology and Experimental Therapeutics June 1, 2001, 297 (3) 861-867;
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