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Vol. 292, Issue 3, 1146-1152, March 2000
Departments of Biopharmaceutical Sciences (M.J.D., K.M.G.) and
Anesthesia (A.T.G.), University of California, San Francisco,
California
Organic cation transporters play an important role in the absorption,
distribution, and elimination of clinical agents, toxic substances, and
endogenous compounds. In kidney preparations, significant differences
in functional characteristics of organic cation transport between
various species have been reported. However, the underlying molecular
mechanisms responsible for these interspecies differences are not
known. The goal of this study was to determine the kinetics and
substrate selectivities of organic cation transporter (OCT1) homologs
from mouse, rat, rabbit, and human that may contribute to interspecies
differences in the renal and hepatic handling of organic cations. With
a series of n-tetraalkylammonium (nTAA) compounds, a
correlation between increasing alkyl chain length and affinity for the
four OCT1 homologs was observed. However, the apparent affinity
constants (Ki) differed among the species homologs. For the mouse homolog mOCT1, apparent
Ki values ranged from 7 µM for
tetrabutylammonium to 2000 µM for tetramethylammonium. In contrast,
the human homolog hOCT1 exhibited weaker interactions with the nTAA
compounds. Trans-stimulation studies and current measurements in voltage-clamped oocytes demonstrated that larger nTAA
compounds were transported at greater rates in oocytes expressing hOCT1, whereas smaller nTAAs were transported at greater rates in
oocytes expressing mOCT1 or rOCT1. The rabbit homolog rbOCT1 exhibited
intermediate properties in its interactions with nTAAs compared with
its rodent and human counterparts. This report demonstrates that the
human OCT1 homolog has functional properties distinct from those of the
rodent and rabbit OCT1 homologs. The study underscores potential
difficulties in extrapolating data from preclinical studies in animal
models to humans.
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