AJP - Gastrointestinal and Liver Physiology, Vol 253, Issue 5 613-G621, Copyright © 1987 by American Physiological Society
Effects of chlorpromazine on Na+-K+-ATPase pumping and solute transport in rat hepatocytes
R. W. Van Dyke and B. F. Scharschmidt
Liver Center, University of California, San Francisco 94143.
Inhibition of Na+-K+-ATPase and sodium-dependent bile acid transport has
been suggested as a mechanism for the cholestasis produced by certain drugs
such as chlorpromazine. We examined the effects of chlorpromazine (and in
selected studies, two of its metabolites) on Na+-K+-ATPase cation pumping
(ouabain-suppressible 86Rb uptake), exchangeable intracellular sodium
content, membrane potential (assessed by 36Cl- distribution), and
sodium-dependent transport of taurocholate and alanine in primary cultures
of rat hepatocytes. Chlorpromazine (10-300 microM),
7,8-dihydroxychlorpromazine (10-300 microM), and ouabain (0.1-2 mM), but
not chlorpromazine sulfoxide, produced a concentration-dependent decrease
in Na+-K+-ATPase cation pumping and an increase in intracellular sodium
content. Chlorpromazine (100 microM) and ouabain (0.75 mM) also modestly
decreased hepatocyte membrane potential. In further studies, chlorpromazine
(75 and 100 microM) and ouabain (0.1, 0.5, and 0.75 mM) decreased initial
sodium-dependent uptake rates of taurocholate and alanine by 18-63%.
Although the steady-state intracellular content of alanine was decreased
25-53% by both agents, chlorpromazine increased the steady-state content of
taurocholate by 171% and decreased taurocholate efflux, apparently related
to partitioning of taurocholate into a large, slowly turning over
intracellular pool. These studies provide direct evidence that
chlorpromazine inhibits Na+-K+-ATPase cation pumping in intact cells and
that partial inhibition of Na+-K+-ATPase cation pumping is associated with
a reduction of both the electrochemical sodium gradient and
sodium-dependent solute transport. These effects of chlorpromazine may
contribute to chlorpromazine-induced cholestasis in animals and humans.
