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Vol. 298, Issue 3, 1179-1184, September 2001
Graduate School of Pharmaceutical Sciences (N.M., H.K., Y.S.) and
Department of Pediatrics (T.S.), The University of Tokyo, Tokyo, Japan;
Department of Pharmacology and Toxicology, Kyorin University School of
Medicine, Tokyo, Japan (H.E.); and Core Research for Evolutional
Science and Technology (CREST), Japan Science and Technology
Corporation, Tokyo, Japan (H.K., Y.S.)
Rat organic anion transporter 2 (rOat2) is abundantly expressed in the
liver and localized to the basolateral membrane. A previous
study using the Xenopus laevis oocyte expression system has shown that rOat2 transports organic anions such as salicylate (Sekine et al., 1998) and, in the present study, rOat2 was
characterized using a mammalian expression system. In addition to the
substrates previously shown to be transported by rOat2, three
substrates, indomethacin [IDM, Michaelis-Menten constant
(Km) of 0.37 µM] and nucleoside
derivatives such as 3'-azido-3'-deoxythymidine (AZT,
Km of 26 µM) and 2',3'-dideoxycytidine
(ddC, Km of 3.08 mM), were also identified
for the first time The rank order of rOat2-mediated transport of these
substrates was IDM > salicylate > prostaglandin
E2 > AZT > ddC > p-aminohippurate (PAH). Ketoprofen, indocyanine green
and glibenclamide are potent inhibitors of the uptake of
[14C]salicylate via rOat2 (Ki
of ~12 µM), while diclofenac, benzoate, verapamil, ibuprofen, and
tolbutamide are moderate inhibitors (Ki of
~150 µM). The affinity of PAH, a common substrate for the OAT
family, for rOat2 is low (Ki > 1 mM)
compared with the other members of the OAT family (rOat1 and rOat3).
Salicylate and IDM are also substrates for rOat1, but their affinity
for rOat2 was higher than that for rOat1. The present study shows that
rOat2 is a multispecific transporter and suggests that it may be
involved at least partly, in the hepatic uptake of IDM, salicylate and nucleoside derivatives.
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