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Vol. 289, Issue 2, 1104-1111, May 1999
Department of Pharmacology, Faculty of Medical Sciences, University
of Nijmegen, Nijmegen, the Netherlands (R.M., M.M.M., F.G.M.R.); and
Laboratory of Pharmacology and Chemistry, National Institute of
Environmental Health Sciences, National Institutes of Health, Research
Triangle Park, North Carolina (B.H.T., D.S.M.)
Recent studies show that organic anion secretion in renal proximal
tubule is mediated by distinct sodium-dependent and sodium-independent transport systems. Here we investigated the possibility that organic anions entering the cells on one system can exit into the lumen on a
transporter associated with the other system. In isolated rat kidneys
perfused with 10 µM lucifer yellow (LY, a fluorescent organic anion)
plus 100 µg/ml inulin, the LY-to-inulin clearance ratio averaged
1.6 ± 0.2, indicating net tubular secretion. Probenecid significantly reduced both LY clearance and LY accumulation in kidney
tissue. In intact killifish proximal tubules, confocal microscopy was
used to measure steady-state LY uptake into cells and secretion into
the tubular lumen. Probenecid, p-aminohippurate, and
ouabain nearly abolished both uptake and secretion. To this point, the
data indicated that LY was handled by the sodium-dependent and
ouabain-sensitive organic anion transport system. However, leukotriene
C4, an inhibitor of the luminal step for the
sodium-independent and ouabain-insensitive organic anion system,
reduced luminal secretion of LY by 50%. Leukotriene C4 did
not affect cellular accumulation of LY or the transport of fluorescein
on the sodium-dependent system. A similar inhibition pattern was found
for another fluorescent organic anion, a mercapturic acid derivative of
monochlorobimane. Thus, both organic anions entered the cells on the
basolateral transporter for the classical, sodium-dependent system, but
about half of the transport into the lumen was handled by the luminal carrier for the sodium-independent system, which is most likely the
multidrug resistance-associated protein. This is the first demonstration that xenobiotics can enter renal proximal tubule cells on
the carrier associated with one organic anion transport system and exit
into the tubular lumen on multiple carriers, one of which is associated
with a second system.
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