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-meth ylglutaryl 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 muM. The uptake of pravastatin was temperature-dependent and was inhibited by estradiol-17 beta -D-glucuronide, taurocholic acid, bromosulf ophthalein, and simvastatin acid, but not by p-aminohippurate. Estradiol-17 beta -D-glucuronide competitively inhibited pravastatin uptake with an inh ibition constant comparable to the K-m value for estradiol-17 beta -D-glucu ronide transport, indicating that a common transporter mediates the transpo rt of pravastatin and estradiol-17 beta -D-glucuronide in human hepatocytes . The results obtained with human hepatocytes agreed with those obtained wi th LST-1 expressing Xenopus oocytes. Oocytes microinjected with human liver polyadenylated mRNA showed Na+-independent uptake of pravastatin and estra diol-17 beta -D-glucuronide. A simultaneous injection of LST-1 antisense ol igonucleotides completely abolished this uptake. Expression of LST-1 was im munohistochemically demonstrated in the human hepatocytes, but not in Hep G 2 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.