Preclinical/Animal Transporters

Ntcp - cynomolgus monkey

Ntcp (sodium/taurocholate cotransporting polypeptide), rat and cynomolgus monkey

Aliases: Ntcp1, SBACT
Gene name: Solute carrier family 10 member 1 (Slc10a1)

Similar to its human counterpart, rat Ntcp is localized to the basolateral membrane of hepatocytes, whereas the localization of Ntcp in the liver of the cynomolgus monkey has not yet been established. Rat and monkey orthologues share 77% and 96% amino acid homology, respectively, with the human protein [1-3]. The rat transporter consists of 362 amino acids (molecular mass 39 kDa) with five possible N-linked glycosylation sites and seven transmembrane domains. Its operation is strictly sodium-dependent [4].

Based on data from Sprague-Dawley and Wistar rats, rNtcp expression is significantly, 4-5-fold higher than in humans. In cynomolgus monkey, the absolute abundance of Ntcp protein in the liver is similar to humans, although its expression relative to other liver transporters is lower [5].

Considering how widely this species is used in the study of transporter-mediated DDI, data on cynomolgus monkey Ntcp are surprisingly scarce. In vivo experiments showed that rosuvastatin and atorvastatin are substrates of cNtcp, and rifampicin acted as a weak inhibitor with a potency 10 times lower than in humans [6].

The substrate range of rNtcp is similar to that of the human orthologue and includes unconjugated bile salts along with glycocholic, taurocholic, tauroursodeoxycholic and taurochenodeoxycholic acid, as well as some non-bile-acid organic anions such as estrone-3 sulfates [7-9]. Rosuvastatin, on the other hand, is a substrate for NTCP but not rNtcp [10].

Cyclosporine A, probenecide, rifampicin, and rifamycin are known inhibitors of both rNtcp and the human protein [9], but species differences in inhibition profile have also been observed. For example, administration of bosentan results in less intrahepatocytic accumulation of bile acids in rats compared to humans. In vitro experiments have proven that bosentan is a more potent inhibitor of taurocholate uptake on rNtcp than human NTCP, which explains the insensitivity of the rat model to bosentan-induced hepatotoxicity [11].

rNtcp expression has been shown to be under multihormonal control involving thyroid hormone, corticosterone, and growth hormone, and exhibits a sexually dimorphic pattern [12]. The modulation of rNtcp/NTCP expression in long-term (5-9 days) sandwich-cultured hepatocytes was investigated in human and rat hepatocytes. rNtcp expression was significantly down-regulated to 10-50% of initial levels at the beginning of culture and stayed persistently low, while no similar effect of sandwich culturing on NTCP levels was seen in human hepatocytes [13, 14]. Monoammonium glycyrrhizinate, a compound commonly used for hepatic protection due to its ability to alter the expression of several transporter proteins, was shown to elevate rNtcp levels in vivo [15].

References

1.    Hagenbuch, B. and P.J. Meier, Molecular cloning, chromosomal localization, and functional characterization of a human liver Na+/bile acid cotransporter. J Clin Invest, 1994. 93(3): p. 1326-31.
2.    Stieger, B., et al., In situ localization of the hepatocytic Na+/Taurocholate cotransporting polypeptide in rat liver. Gastroenterology, 1994. 107(6): p. 1781-7.
3.    Yan, H., et al., Sodium taurocholate cotransporting polypeptide is a functional receptor for human hepatitis B and D virus. Elife, 2012. 1: p. e00049.
4.    Hagenbuch, B., et al., Functional expression cloning and characterization of the hepatocyte Na+/bile acid cotransport system. Proc Natl Acad Sci U S A, 1991. 88(23): p. 10629-33.
5.    Wang, L., et al., Interspecies variability in expression of hepatobiliary transporters across human, dog, monkey, and rat as determined by quantitative proteomics. Drug Metab Dispos, 2015. 43(3): p. 367-74.
6.    Chu, X., et al., Evaluation of cynomolgus monkeys for the identification of endogenous biomarkers for hepatic transporter inhibition and as a translatable model to predict pharmacokinetic interactions with statins in humans. Drug Metab Dispos, 2015. 43(6): p. 851-63.
7.    Hata, S., et al., Substrate specificities of rat oatp1 and ntcp: implications for hepatic organic anion uptake. Am J Physiol Gastrointest Liver Physiol, 2003. 285(5): p. G829-39.
8.    Mita, S., et al., Vectorial transport of unconjugated and conjugated bile salts by monolayers of LLC-PK1 cells doubly transfected with human NTCP and BSEP or with rat Ntcp and Bsep. Am J Physiol Gastrointest Liver Physiol, 2006. 290(3): p. G550-6.
9.    Schroeder, A., et al., Substrate specificity of the rat liver Na(+)-bile salt cotransporter in Xenopus laevis oocytes and in CHO cells. Am J Physiol, 1998. 274(2 Pt 1): p. G370-5.
10.    Ho, R.H., et al., Drug and bile acid transporters in rosuvastatin hepatic uptake: function, expression, and pharmacogenetics. Gastroenterology, 2006. 130(6): p. 1793-806.
11.    Leslie, E.M., et al., Differential inhibition of rat and human Na+-dependent taurocholate cotransporting polypeptide (NTCP/SLC10A1)by bosentan: a mechanism for species differences in hepatotoxicity. J Pharmacol Exp Ther, 2007. 321(3): p. 1170-8.
12.    Simon, F.R., et al., Multihormonal regulation of hepatic sinusoidal Ntcp gene expression. Am J Physiol Gastrointest Liver Physiol, 2004. 287(4): p. G782-94.
13.    Borlak, J. and T. Klutcka, Expression of basolateral and canalicular transporters in rat liver and cultures of primary hepatocytes. Xenobiotica, 2004. 34(11-12): p. 935-47.
14.    Qiu, X., et al., Absolute measurement of species differences in sodium taurocholate cotransporting polypeptide (NTCP/Ntcp) and its modulation in cultured hepatocytes. J Pharm Sci, 2013. 102(9): p. 3252-63.
15.    Zhou, L., et al., Monoammonium glycyrrhizinate protects rifampicin- and isoniazid-induced hepatotoxicity via regulating the expression of transporter Mrp2, Ntcp, and Oatp1a4 in liver. Pharm Biol, 2016. 54(6): p. 931-7.

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