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1 Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, NY, USA
2 Department of Pediatrics, Mt. Sinai School of Medicine, New York, NY, USA
3 Department of Medicine, Division of Gastroenterology, University of Medicine and Dentistry of New Jersey, New Jersey Medical School and GI Research Lab, VA Medical Center, Newark, NJ, USA
4 Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada
* To whom correspondence should be addressed. E-mail: wolkoff{at}aecom.yu.edu.
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 ntcp or 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 non-conjugated bile acids, and the configuration of the hydroxyl groups (
or 
) had little influence on uptake. Although cholic and 23-nor-cholic 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 4-8 fold below that of the corresponding dihydroxy conjugates. Ntcp mediated high affinity, sodium-dependent transport of 35S-sulfobromophthalein with a Km similar to that of oatp1-mediated transport of 35S-sulfobromophthalein (Km = 3.7 µM 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 physiologic function in vivo.
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