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Vol. 288, Issue 3, 1192-1198, March 1999
Department of Biopharmaceutical Sciences, University of California
San Francisco, San Francisco, California
Polyspecific organic cation transporters in epithelia play an important
role in the elimination of many endogenous bioactive amines and
therapeutically important drugs. Recently, the first human organic
cation transporter (hOCT1) was cloned from liver. The purpose of the
current study was to determine the effect of molecular size and
hydrophobicity on the transport of organic cations by hOCT1. We studied
the interaction of a series of n-tetraalkylammonium (n-TAA) compounds (alkyl chain length, N, ranging from 1 to 6 carbons) with hOCT1 in a transiently transfected human cell line, HeLa. [14C]tetraethylammonium (TEA) uptake was measured
under different experimental conditions. Both
cis-inhibition and trans-stimulation studies were carried out. With the exception of
tetramethylammonium, all of the n-TAAs
significantly inhibited [14C]TEA uptake. A reversed
correlation of IC50 values (range, 3.0-260 µM) with
alkyl chain lengths or partition coefficients (LogP) was observed.
trans-Stimulation studies revealed that TEA,
tetrapropylammonium, tetrabutylammonium, as well as
tributylmethylammonium trans-stimulated TEA uptake
mediated by hOCT1. In contrast, tetramethylammonium and
tetrapentylammonium did not trans-stimulate
[14C]TEA uptake, and tetrahexylammonium demonstrated an
apparent "trans-inhibition" effect. These data
indicate that with increasing alkyl chain lengths (N 
2),
n-TAA compounds are more poorly translocated by hOCT1
although their potency of inhibition increases. Similar findings were
obtained with nonaliphatic hydrocarbons. These data suggest that a
balance between hydrophobic and hydrophilic properties is necessary for
binding and subsequent translocation by hOCT1.
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