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Vol. 291, Issue 3, 1204-1209, December 1999
Division of Clinical Pharmacology, Departments of Medicine and
Pharmacology, Vanderbilt University School of Medicine, Nashville,
Tennessee
Adequate bile flow, maintained in part by the efficient
enterohepatic recirculation of bile acids, is critical for normal liver
function. One important component of this process is the uptake of bile
acids from the portal circulation into hepatocytes by the bile acid
uptake transporter sodium taurocholate cotransporting polypeptide
(NTCP). Thus, the expression and functional activity of this
transporter may affect the rate of bile acid removal from the portal
circulation. Accordingly, we assessed NTCP mRNA
expression from human livers using a sensitive RNase protection assay.
In addition, the ability of various bile acids and drugs to inhibit NTCP activity was determined using a recombinant vaccinia expression system. A 40-fold interindividual variability was found in
NTCP mRNA levels determined in eight liver samples of
disease-free donors. Expressed NTCP exhibited high-affinity,
sodium-dependent uptake of taurocholate, and as expected, this was
markedly inhibited by bile acids and organic anions. A number of drugs,
including peptidomimetic renin inhibitors, propranolol, cyclosporin,
and progesterone, were found to be potent inhibitors, whereas
antiarrhythmic agents, including bupivicaine, lidocaine, and quinidine,
were found to enhance NTCP activity. Accordingly, these results
indicate that large interindividual variability exists in NTCP mRNA
level and that a number of drugs currently in clinical use have the potential to interact with and alter NTCP activity, thereby affecting hepatic bile acid uptake.
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