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LIVER AND BILIARY TRACT

Substrate specificities of rat oatp1 and ntcp: implications for hepatic organic anion uptake

¹Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx 10461; ²Department of Pediatrics, Mt. Sinai School of Medicine, New York, New York 10029; ³Department of Medicine, Division of Gastroenterology, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark 07103; Gastrointestinal Research Laboratory, Veterans Affairs Medical Center, East Orange, New Jersey 07018; and ⁴Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada M5S 2S2

Submitted 20 August 2002 ; accepted in final form 26 June 2003

Transport of a series of ³H-radiolabeled C₂₃, C₂₄, and C₂₇ bile acid derivatives was compared and contrasted in HeLa cell lines stably transfected with rat Na⁺/taurocholate cotransporting polypeptide (ntcp) or organic anion transporting polypeptide 1 (oatp1) in which expression was under regulation of a zinc-inducible promoter. Similar uptake patterns were observed for both ntcp and oatp1, except that unconjugated hyodeoxycholate was a substrate of oatp1 but not ntcp. Conjugated bile acids were transported better than nonconjugated bile acids, and the configuration of the hydroxyl groups ( or ) had little influence on uptake. Although cholic and 23 norcholic acids were transported by ntcp and oatp1, other unconjugated bile acids (chenodeoxycholic, ursodeoxycholic) were not. In contrast to ntcp, oatp1-mediated uptake of the trihydroxy bile acids taurocholate and glycocholate was four- to eightfold below that of the corresponding dihydroxy conjugates. Ntcp mediated high affinity, sodium-dependent transport of [³⁵S]sulfobromophthalein with a K_m similar to that of oatp1-mediated transport of [³⁵S]sulfobromophthalein (K_m = 3.7 vs. 3.3 µM, respectively). In addition, for both transporters, uptake of sulfobromophthalein and taurocholic acid showed mutual competitive inhibition. These results indicate that the substrate specificity of ntcp is considerably broader than previously suspected and caution the extrapolation of transport data obtained in vitro to physiological function in vivo.

hepatocyte; cell transfection

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