Substrate specificities of rat oatp1 and ntcp

Implications for hepatic organic anion uptake

Soichiro Hata, Pijun Wang, Nicole Eftychiou, Meenakshisundaram Ananthanarayanan, Ashok Batta, Gerald Salen, K. Sandy Pang, Allan W. Wolkoff

Research output: Contribution to journalArticle

68 Citations (Scopus)

Abstract

Transport of a series of 3H-radiolabeled C23, C 24, 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 (α or β) 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 Km similar to that of oatp1-mediated transport of [ 35S] sulfobromophthalein (Km = 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.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Gastrointestinal and Liver Physiology
Volume285
Issue number5 48-5
StatePublished - Nov 2003

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Taurocholic Acid
Substrate Specificity
Anions
Peptides
Liver
Bile Acids and Salts
Sulfobromophthalein
Glycocholic Acid
HeLa Cells
Hydroxyl Radical
Zinc
Sodium

Keywords

  • Cell transfection
  • Hepatocyte

ASJC Scopus subject areas

  • Gastroenterology
  • Physiology

Cite this

Substrate specificities of rat oatp1 and ntcp : Implications for hepatic organic anion uptake. / Hata, Soichiro; Wang, Pijun; Eftychiou, Nicole; Ananthanarayanan, Meenakshisundaram; Batta, Ashok; Salen, Gerald; Pang, K. Sandy; Wolkoff, Allan W.

In: American Journal of Physiology - Gastrointestinal and Liver Physiology, Vol. 285, No. 5 48-5, 11.2003.

Research output: Contribution to journalArticle

Hata, Soichiro ; Wang, Pijun ; Eftychiou, Nicole ; Ananthanarayanan, Meenakshisundaram ; Batta, Ashok ; Salen, Gerald ; Pang, K. Sandy ; Wolkoff, Allan W. / Substrate specificities of rat oatp1 and ntcp : Implications for hepatic organic anion uptake. In: American Journal of Physiology - Gastrointestinal and Liver Physiology. 2003 ; Vol. 285, No. 5 48-5.
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AU - Eftychiou, Nicole

AU - Ananthanarayanan, Meenakshisundaram

AU - Batta, Ashok

AU - Salen, Gerald

AU - Pang, K. Sandy

AU - Wolkoff, Allan W.

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AB - Transport of a series of 3H-radiolabeled C23, C 24, 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 (α or β) 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 Km similar to that of oatp1-mediated transport of [ 35S] sulfobromophthalein (Km = 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.

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