HEPATOCANALICULAR ORGANIC-ANION TRANSPORT IS REGULATED BY PROTEIN-KINASE-C

In order to investigate the regulation of canalicular organic-anion transport, we used a hepatocyte transport assay in which canalicular secretion of a model organic anion, dinitrophenyl-glutathione (GS-DNP), was measured in the presence of stimulators and inhibitors of the Ca2+/protein kinase C (PKC) second-messenger system and of the cyclic AMP (cAMP) second-messenger system. Vasopressin (24 nM) and the phorbol ester phorbol 12-myristate 13-acetate (1-mu-g/ml), both stimulators of PKC, stimulated GS-DNP efflux by 65 +/- 36 % and 55 +/- 28 % respectively, whereas staurosporine (10-mu-M), an inhibitor of PKC, inhibited efflux by 53 +/- 13 %. Glucagon and forskolin, both stimulators of the cAMP second-messenger system, as well as the cAMP analogue dibutyrul cAMP and the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine, did not significantly influence the GS-DNP efflux. It can be concluded that canalicular organic-anion transport in hepatocytes is either directly or indirectly regulated by PKC.