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J Biol Chem, Vol. 273, Issue 26, 16184-16191, June 26, 1998
From the oatp1 is an hepatic sinusoidal organic anion
transporter that mediates uptake of various structurally unrelated
organic compounds from blood. The driving force for uptake on oatp1 has
not been identified, although a role for bicarbonate has recently been proposed. The present study examined whether oatp1-mediated uptake is
energized by efflux (countertransport) of intracellular reduced glutathione (GSH), and whether hydrophobic glutathione
S-conjugates such as leukotriene C4
(LTC4) and S-dinitrophenyl glutathione (DNP-SG)
form a novel class of substrates for oatp1. Xenopus laevis oocytes injected with the complementary RNA for oapt1 demonstrated higher uptake of 10 nM [3H]LTC4
and 50 µM [3H]DNP-SG, and higher efflux of
[3H]GSH (2.5 mM endogenous intracellular GSH
concentration). The oatp1-stimulated LTC4 and DNP-SG uptake
was independent of the Na+ gradient,
cis-inhibited by known substrates of this transport protein
and by 1 mM GSH, and was saturable, with apparent
Km values of 0.27 ± 0.06 and 408 ± 95 µM, respectively. Uptake of [3H]taurocholate, an endogenous substrate of oatp1, was
competitively inhibited by DNP-SG. Of significance, oatp1-mediated
taurocholate and LTC4 uptake was cis-inhibited
and trans-stimulated by GSH, and [3H]GSH
efflux was enhanced in the presence of extracellular taurocholate or
sulfobromophthalein, indicating that GSH efflux down its large electrochemical gradient provides the driving force for uptake via
oatp1. The stoichiometry of GSH/taurocholate exchange was 1:1. These
findings identify a new class of substrates for oatp1 and provide
evidence for GSH-dependent oatp1-mediated substrate transport.
Identification of Glutathione as a Driving Force and
Leukotriene C4 as a Substrate for oatp1, the Hepatic
Sinusoidal Organic Solute Transporter
,,
Department of Environmental Medicine,
University of Rochester School of Medicine, Rochester, New York 14642 and the § Division of Clinical Pharmacology and Toxicology,
Department of Medicine, University Hospital,
CH-8091 Zürich, Switzerland
Copyright © 1998 by The American Society for Biochemistry and Molecular Biology, Inc.
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