RT Journal Article
SR Electronic
T1 Human Liver-Specific Organic Anion Transporter, LST-1, Mediates Uptake of Pravastatin by Human Hepatocytes
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 861
OP 867
VO 297
IS 3
A1 Nakai, Daisuke
A1 Nakagomi, Rie
A1 Furuta, Yoshitake
A1 Tokui, Taro
A1 Abe, Takaaki
A1 Ikeda, Toshihiko
A1 Nishimura, Kenji
YR 2001
UL http://jpet.aspetjournals.org/content/297/3/861.abstract
AB 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. The American Society for Pharmacology and Experimental Therapeutics