A novel human hepatic organic anion transporting polypeptide (OATP2). Identification of a liver-specific human organic anion transporting polypeptide and identification of rat and human hydroxymethylglutaryl-CoA reductase inhibitor transporters.
A novel human organic transporter, OATP2, has been identified that transports taurocholic acid, the adrenal androgen dehydroepiandrosterone sulfate, and thyroid hormone, as well as the hydroxymethylglutaryl-CoA reductase inhibitor, pravastatin. OATP2 is expressed exclusively in liver in contrast to all other known transporter subtypes that are found in both hepatic and nonhepatic tissues. OATP2 is considerably diverged from other family members, sharing only 42% sequence identity with the four other subtypes. Furthermore, unlike other subtypes, OATP2 did not transport digoxin or aldosterone. The rat isoform oatp1 was also shown to transport pravastatin, whereas other members of the OATP family, i.e. rat oatp2, human OATP, and the prostaglandin transporter, did not. Cis-inhibition studies indicate that both OATP2 and roatp1 also transport other statins including lovastatin, simvastatin, and atorvastatin. In summary, OATP2 is a novel organic anion transport protein that has overlapping but not identical substrate specificities with each of the other subtypes and, with its liver-specific expression, represents a functionally distinct OATP isoform. Furthermore, the identification of oatp1 and OATP2 as pravastatin transporters suggests that they are responsible for the hepatic uptake of this liver-specific hydroxymethylglutaryl-CoA reductase inhibitor in rat and man.
Hsiang
B
B
Bristol-Myers Squibb Co., Pharmaceutical Research Institute, Princeton, New Jersey 08543-4000, USA.
Zhu
Y
Y
Wang
Z
Z
Wu
Y
Y
Sasseville
V
V
Yang
W P
WP
Kirchgessner
T G
TG
D000595:Amino Acid Sequence; D000818:Animals; D027321:Anion Transport Proteins; D001483:Base Sequence; D001692:Biological Transport; D002352:Carrier Proteins / Q000302:isolation & purification* / Q000502:physiology; D019314:Dehydroepiandrosterone Sulfate / Q000493:pharmacokinetics; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000493:pharmacokinetics*; D008099:Liver / Q000378:metabolism*; D008969:Molecular Sequence Data; D017035:Pravastatin / Q000493:pharmacokinetics; D051381:Rats; D013656:Taurocholic Acid / Q000493:pharmacokinetics
D027321:Anion Transport Proteins; D002352:Carrier Proteins; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D019314:Dehydroepiandrosterone Sulfate; D013656:Taurocholic Acid; D017035:Pravastatin