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Modulators of the protein kinase C system influence biliary excretion of cationic drugs
1Department of Pharmacology and Therapeutics, Groningen State University, The Netherlands.
Abstract:
To investigate whether hepatobiliary transport of organic cations is under regulatory control, we studied transport of tri-n-butylmethylammonium in the isolated perfused rat liver and in isolated rat hepatocytes. Transport was investigated in the presence of modulators of the protein kinase C and the cyclic AMP second-messenger system. In the isolated perfused rat liver, it was observed that compounds modulating protein kinase C activity clearly affected the biliary excretion process of the cation tri-n-butylmethylammonium. Phorbol 12-myristate 13-acetate, a compound that directly stimulates protein kinase C, elevated the biliary excretion rate of tri-n-butylmethylammonium in a concentration-dependent manner, reaching a twofold increase at 60 nmol/L of the phorbol ester. The inactive derivative 4 alpha-phorbol 12, 13-didecanoate (60 nmol/L) did not show any effect. Vasopressin (48 nmol/L), a receptor-mediated activator of protein kinase C, stimulated the excretion rate of the cation by about 50%. Staurosporin (1 mumol/L), an inhibitor of protein kinase C, clearly decreased the biliary excretion rate of the cation and also blocked its stimulation by phorbol 12-myristate 13-acetate. Neither phorbol 12-myristate 13-acetate nor vasopressin (at concentrations ranging from 10(-9) to 10(-6) mol/L) affected the initial uptake velocity of tri-n-butylmethylammonium in isolated hepatocytes and isolated perfused livers, whereas staurosporin (1 mumol/L) showed only a modest inhibition of the uptake of the cation. It is inferred that the effect of protein kinase C modulators on hepatobiliary transport of organic cations occurs at the level of carrier-mediated transport in the canalicular membrane.(ABSTRACT TRUNCATED AT 250 WORDS)
Insights
Hepatobiliary transport of organic cations is regulated by protein kinase C. Modulators of this system significantly impact the biliary excretion of tri-n-butylmethylammonium in rats.
Area of Science:
- Hepatobiliary Transport
- Cellular Signaling
- Pharmacology
Background:
- Organic cation transport in the liver is crucial for xenobiotic and endogenous compound elimination.
- The regulatory mechanisms governing hepatobiliary transport of organic cations remain incompletely understood.
- Protein kinase C (PKC) and cyclic AMP (cAMP) are key intracellular signaling pathways involved in cellular regulation.
Purpose of the Study:
- To investigate whether hepatobiliary transport of organic cations is under regulatory control.
- To examine the role of protein kinase C and cyclic AMP signaling in the regulation of organic cation biliary excretion.
Main Methods:
- Transport of tri-n-butylmethylammonium (TBMA) was studied in isolated perfused rat liver and isolated rat hepatocytes.
- Experiments involved the use of modulators of protein kinase C (phorbol esters, vasopressin, staurosporine) and the cAMP system.
- Biliary excretion rates and initial uptake velocities of TBMA were measured.
Main Results:
- Modulators of protein kinase C significantly affected the biliary excretion of tri-n-butylmethylammonium.
- Phorbol 12-myristate 13-acetate (a PKC activator) increased TBMA biliary excretion dose-dependently.
- Vasopressin (a PKC activator) stimulated TBMA excretion by approximately 50%, while staurosporine (a PKC inhibitor) decreased it.
- PKC modulation primarily affected canalicular transport, not the initial uptake of TBMA into hepatocytes.
Conclusions:
- Hepatobiliary transport of organic cations, exemplified by TBMA, is under regulatory control.
- Protein kinase C plays a significant role in modulating the biliary excretion of organic cations.
- The regulatory effect of PKC modulators occurs at the level of carrier-mediated transport in the canalicular membrane.