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Vol. 58, Issue 2, 335-340, August 2000
Department of Environmental Medicine, University of Rochester
School of Medicine, Rochester, New York (L.L., N.B.); and Division of
Clinical Pharmacology and Toxicology, Department of Medicine,
University Hospital, Zürich, Switzerland (P.J.M.)
One member of the OATP family of transporters, rat Oatp1, functions as
an anion exchanger that is driven in part by the glutathione (GSH)
electrochemical gradient, indicating that other OATP-related transporters may also be energized by this mechanism. The present study
examined whether rat Oatp2 is also an anion exchanger, and, if so,
whether it is energized by the GSH electrochemical gradient. As with
Oatp1, uptake of 10 µM [3H]taurocholate in
Oatp2-expressing Xenopus laevis oocytes was trans-stimulated by intracellular 0.2 mM unlabeled
taurocholate, indicating bidirectional transport. Interestingly,
[3H]taurocholate uptake in Oatp2-expressing oocytes was
also trans-stimulated when oocytes were preloaded with
GSH, S-methylglutathione,
S-sulfobromophthalein-glutathione, S-dinitrophenyl glutathione, or ophthalmic acid (a GSH
analog) but not by glutarate or N-acetylcysteine,
suggesting that GSH derivatives and conjugates may function as
intracellular substrates for Oatp2. Support for this hypothesis was
provided by the demonstration of enhanced [3H]GSH and
[3H]S-(2,4-dinitrophenyl)-glutathione
efflux in Oatp2-expressing oocytes. However, in contrast to Oatp1,
extracellular GSH failed to cis-inhibit uptake of
[3H]taurocholate or [3H]digoxin in
Oatp2-expressing oocytes, indicating that the stimulatory effect of
high intracellular GSH concentrations is not due to a coupled exchange
mechanism. Taken together, the results indicate that Oatp2 mediates
bidirectional transport of organic anions by a GSH-sensitive
facilitative diffusion mechanism and suggest that this transporter may
play a role in cellular export of specific organic molecules.
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