TRANSPORT OF SMALL ORGANIC CATIONS IN THE RAT-LIVER - THE ROLE OF THEORGANIC CATION TRANSPORTER OCT1

The kidneys and the liver are the principal organs for the inactivatio n of circulating organic cations. Recently, an organic cation transpor ter (OCT1) has been cloned from rat kidney. In order to answer the que stion whether OCT1 is involved also in hepatic uptake of organic catio ns, the pharmacological characteristics of organic cation transport in hepatocytes were compared to the characteristics of transiently expre ssed OCT1. Primary cultures of rat hepatocytes avidly accumulated the small organic cation H-3-1-methyl-4-phenylpyridinium (H-3-MPP(+)). At equilibrium, the hepatocytes accumulated H-3-MPP(+) 56-fold. Initial r ates of specific H-3-MPP(+) transport in hepatocytes were saturable. T he half-saturating concentration was 13 mu mol/l. H-3-MPP(+) transport was sensitive to quinine (K-i = 0.79 mu mol/l) and cyanine863 (K-i = 0.097 mu mol/l). Quinine and cyanine863 are known inhibitors of type I hepatic transport of cationic drugs and of renal excretion of organic cations, respectively. To compare the functional characteristics of H -3-MPP(+) transport in hepatocytes with those of OCT1, OCT1 has been h eterologously expressed and characterized in a mammalian cell line (29 3 cells). Initial rates of H-3-MPP(+) transport were saturable, the K- m being 13 mu mol/l. The rank order of inhibitory potencies of various inhibitors was almost identical in hepatocytes and 293 cells transien tly transfected with OCT1. There was a positive correlation between th e K-i's for the inhibition of H-3-MPP(+) transport in isolated hepatoc ytes and transfected 293 cells (r = 0.85; P<0.01; n = 8). The results indicate that OCT1 is functionally expressed not only in the kidney bu t also in hepatocytes where it is responsible for the transport of sma ll organic cations which, in the past, have been classified as type I substrates.