Human liver-specific organic anion transporter, LST-1, mediates uptake of pravastatin by human hepatocytes.
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 (K(m)) of 11.5 +/- 2.2 microM. The uptake of pravastatin was temperature-dependent and was inhibited by estradiol-17beta-D-glucuronide, taurocholic acid, bromosulfophthalein, and simvastatin acid, but not by p-aminohippurate. Estradiol-17beta-D-glucuronide competitively inhibited pravastatin uptake with an inhibition constant comparable to the K(m) value for estradiol-17beta-D-glucuronide transport, indicating that a common transporter mediates the transport of pravastatin and estradiol-17beta-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-17beta-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.
Nakai
D
D
Drug Metabolism and Pharmacokinetics Research Laboratories, Sankyo Co., Ltd., Tokyo, Japan.
Nakagomi
R
R
Furuta
Y
Y
Tokui
T
T
Abe
T
T
Ikeda
T
T
Nishimura
K
K
D000818:Animals; D027321:Anion Transport Proteins; D001692:Biological Transport / Q000187:drug effects; D002250:Carbon Radioisotopes; D006528:Carcinoma, Hepatocellular / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004958:Estradiol / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D005260:Female; D020719:Glucuronides / Q000493:pharmacokinetics; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000493:pharmacokinetics*; D007150:Immunohistochemistry; D009865:Oocytes / Q000166:cytology / Q000378:metabolism; D017035:Pravastatin / Q000493:pharmacokinetics*; D013656:Taurocholic Acid / Q000493:pharmacokinetics; D014316:Tritium; D014982:Xenopus laevis
D027321:Anion Transport Proteins; D002250:Carbon Radioisotopes; D002352:Carrier Proteins; D020719:Glucuronides; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D014316:Tritium; D004958:Estradiol; D013656:Taurocholic Acid; D017035:Pravastatin