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 by p-aminohippurate. Estradiol-17β-D-glucuronide competitively inhibited pravastatin uptake with an inhibition constant comparable to the Km 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 Iow uptake of pravastatin. Therefore, LST-I 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.
|Number of pages||7|
|Journal||Journal of Pharmacology and Experimental Therapeutics|
|Publication status||Published - 2001 Jun|
ASJC Scopus subject areas
- Molecular Medicine