Characterization of the transport properties of organic anion transportingpolypeptide 1 (oatp1) and Na+/taurocholate cotransporting polypeptide (Ntcp): Comparative studies on the inhibitory effect of their possible substrates in hepatocytes and cDNA-transfected COS-7 cells

In the present study, we compared the inhibitory effects of organic anions (including bile acids) on the uptake of taurocholate (TC) and estradiol 17 beta-D-glucuronide (E-2 17 beta G), typical substrates for sodium taurochol ate cotransporting polypeptide (Ntcp) and organic anion transporting polype ptide (oatp1), respectively, using primary cultured rat hepatocytes and Ntc p- or oatp1-transfected COS-7 cells. The Na+-dependent uptake of TC was inh ibited by nine bile acids and five nonbile acid organic anions in a concent ration-dependent manner, and their inhibitory effects were similar in both primary cultured rat hepatocytes and Ntcp-transfected COS-7 cells. BQ-123 ( 1 mu M) and indomethacin (10 mu M), both of which exhibit no Ntcp- mediated transport, significantly inhibited the Na+-dependent uptake of TC mediated by Ntcp. In addition, the Na+-independent uptake of E-2 17 beta G was inhi bited by 15 organic anions in a concentration- dependent manner, and their inhibitory effects were similar between primary cultured rat hepatocytes an d oatp1-transfected COS-7 cells. BQ-123 (1 mu M), pravastatin (1 mu M), and indomethacin (10 mu M), all of which do not undergo oatp1-mediated transpo rt, significantly inhibited the Na+-independent uptake of E-2 17 beta G med iated by oatp1. These results are consistent with the hypothesis that the h epatic uptake of TC and E-2 17 beta G is predominantly mediated by Ntcp and oatp1, respectively. In addition, it was clearly demonstrated that we cann ot refer to the substrate specificity of transporters based on inhibition s tudies.