NTCP

NTCP (sodium/taurocholate cotransporting polypeptide)

Aliases: None
Gene name: Solute carrier family 10 member 1 (SLC10A1)

Summary

NTCP is a sodium-dependent uptake transporter expressed on the basolateral (blood-side) membrane of hepatocytes. It is primarily responsible for the uptake of bile acids from the sinusoids. NTCP is one of the key transporters in the enterohepatic circulation of bile acids; other transporters involved include the canalicular efflux transporter BSEP, as well as ASBT and OSTα/β in the gastrointestinal tract [1]. Although it has restricted specificity for drug substrates, NTCP is relevant to the hepatic uptake of rosuvastatin and therefore is a risk factor for transporter-mediated DDI for this important therapeutic drug. As it is also an important hepatic bile acid transporter, inhibition by drugs may be relevant to hepatotoxicity. However, there are no recommendations for its investigation in the latest FDA and EMA guidances.

Localization

NTCP is located on the basolateral membrane domain (blood-side) of hepatocytes in human, rat and other species [2-4]. NTCP is not detected in any other tissue.

Function, physiology and clinically significant polymorphisms

NTCP is a sodium ion/bile acid cotransporter, with seven predicted transmembrane domains [4]. It is responsible for the basolateral uptake of bile acids from the portal blood into hepatocytes. It is a key component of the enterohepatic recovery of bile acids. In the liver, bile acid uptake by NTCP and OATPs from the portal blood is coupled with apical (biliary) export primarily by BSEP (ABCB11) [5]. Physiological substrates of NTCP include amidated (taurine, glycine) as well as sulfated and unconjugated bile salts [6]. Other substrates include sulfated steroids (estrone-3-sulfate, DHEAS) and thyroid hormones [7]. In comparison with the sodium-independent organic anion transporters of the SLCO family (i.e. OATPs), NTCP interacts with a relatively narrow panel of drugs and other xenobiotics; however, approximately 35% of rosuvastatin hepatic uptake is mediated by NTCP, and this is relevant to the prediction of DDI risks for rosuvastatin [8, 9]. Other statins including fluvastatin, atorvastatin, and pitavastatin are also substrates of human NTCP; however, the clinical relevance of these interactions has not been systematically evaluated [10-12]. In a large screen of 1280 FDA/EMA-approved drugs, rosiglitazone, zafirlukast, TRIAC, sulfasalazine and Chicago sky blue 6B were identified as potent inhibitors (IC50 < 10 μM) of human NTCP-mediated taurocholic acid uptake, and the same compounds also reduced HBV/HDV infection in HepaRG cells [13].
Ethnicity-dependent polymorphisms have been identified and significant interindividual variation in human NTCP mRNA expression levels has been noted [14]. These polymorphisms are linked to decreased NTCP-mediated bile salt transport activity, and thus may potentially play a role in the development of hypercholanemia. To date, only several cases with familial NTCP deficiency have been reported. A girl from a consanguineous Afghani family, homozygous for the SNP p.R252H, presented with extremely elevated plasma total bile salts but no clinical signs of cholestasis [15], and a Chinese male patient homozygous for p.S267F who presented with mild jaundice at 2 months showed no clinical signs on follow-up despite marked hypercholanemia [16]. The inconspicuous clinical course of inherited NTCP deficiency is probably explained by compensatory bile acid transport via OATPs 1B1 and 1B3. A recent study has confirmed that the NCTP p.S267F mutation, a variant specific to Asian populations, is inversely associated with HBV disease progression in Asian chronic hepatitis B patients; therefore, the NTCP p.S267F variant appears to be protective against progression to liver cirrhosis, liver failure and hepatocellular carcinoma in chronic hepatitis B patients [17].

Clinical significance

Although not as promiscuous as many other drug transporters, NTCP is important for mediating the hepatic uptake of the widely prescribed, hepatically acting HMG-CoA reductase inhibitors, in particular rosuvastatin. Inhibition of NTCP is therefore a significant factor in the development of clinically relevant DDIs for rosuvastatin. 
NTCP expression is often downregulated in human liver disease. In liver samples derived from patients with progressive familial intrahepatic cholestasis (PFIC), NTCP was downregulated at the protein level but not the mRNA level, indicating a post-translational regulation of NTCP in PFIC [18]. A reduction in functional NTCP activity resulting from inhibition or decreased expression levels due to physiological and pathophysiological conditions may lead to reduced bile acid uptake and cause cholestasis or hyperbilirubinemia, or exacerbate the existing condition [19].
NTCP is a cell surface receptor necessary for the entry of Hepatitis B and Hepatitis D Viruses [20], and the rs2296651 polymorphism is a risk factor of the susceptibility to, and the chronicity of, HBV infection [21]. Targeting NTCP by Myrcludex B, a synthetic lipopeptide inhibitor of NTCP, efficiently prevents HBV and HDV entry into hepatocytes [22, 23]. Myrcludex B was the first HBV/HDV entry inhibitor targeting NTCP to reach clinical trials where it has also been proposed for the alleviation of hepatobiliary toxicity in cholestatic conditions [24]. It showed a favorable safety profile with low and reversible increase of serum bile salt levels and improvement of biochemical disease activity as indicated by lowered serum ALT. However, in monotherapy Myrcludex B did not display significant antiviral activity [25, 26].

Regulatory requirements

NTCP is relevant to the hepatic uptake of rosuvastatin and hence a risk factor for transporter-mediated DDI for this drug. It is also an important hepatic bile acid transporter, and therefore inhibition by drugs may be relevant to hepatotoxicity. However, there are no recommendations for its investigation in the latest FDA and EMA guidances.

References

1.    Doring, B., et al., The SLC10 carrier family: transport functions and molecular structure. Curr Top Membr, 2012. 70: p. 105-68.
2.    Shneider, B.L., et al., Hepatic basolateral sodium-dependent-bile acid transporter expression in two unusual cases of hypercholanemia and in extrahepatic biliary atresia. Hepatology, 1997. 25(5): p. 1176-83.
3.    Stieger, B., et al., In situ localization of the hepatocytic Na+/Taurocholate cotransporting polypeptide in rat liver. Gastroenterology, 1994. 107(6): p. 1781-7.
4.    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.
5.    Meier, P.J. and B. Stieger, Bile salt transporters. Annu Rev Physiol, 2002. 64: p. 635-61.
6.    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.
7.    Visser, W.E., et al., Study of the transport of thyroid hormone by transporters of the SLC10 family. Mol Cell Endocrinol, 2010. 315(1-2): p. 138-45.
8.    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.
9.    Jamei, M., et al., A Mechanistic Framework for In Vitro-In Vivo Extrapolation of Liver Membrane Transporters: Prediction of Drug-Drug Interaction Between Rosuvastatin and Cyclosporine. Clin Pharmacokinet, 2013.
10.    Fujino, H., et al., Transporter-mediated influx and efflux mechanisms of pitavastatin, a new inhibitor of HMG-CoA reductase. J Pharm Pharmacol, 2005. 57(10): p. 1305-11.
11.    Greupink, R., et al., Interaction of fluvastatin with the liver-specific Na+ -dependent taurocholate cotransporting polypeptide (NTCP). Eur J Pharm Sci, 2011. 44(4): p. 487-96.
12.    Choi, M.K., et al., Differential effect of genetic variants of Na(+)-taurocholate co-transporting polypeptide (NTCP) and organic anion-transporting polypeptide 1B1 (OATP1B1) on the uptake of HMG-CoA reductase inhibitors. Xenobiotica, 2011. 41(1): p. 24-34.
13.    Donkers, J.M., et al., Reduced hepatitis B and D viral entry using clinically applied drugs as novel inhibitors of the bile acid transporter NTCP. Sci Rep, 2017. 7(1): p. 15307.
14.    Ho, R.H., et al., Ethnicity-dependent polymorphism in Na+-taurocholate cotransporting polypeptide (SLC10A1) reveals a domain critical for bile acid substrate recognition. J Biol Chem, 2004. 279(8): p. 7213-22.
15.    Vaz, F.M., et al., Sodium taurocholate cotransporting polypeptide (SLC10A1) deficiency: conjugated hypercholanemia without a clear clinical phenotype. Hepatology, 2015. 61(1): p. 260-7.
16.    Deng, M., et al., Clinical and molecular study of a pediatric patient with sodium taurocholate cotransporting polypeptide deficiency. Exp Ther Med, 2016. 12(5): p. 3294-3300.
17.    Yang, F., et al., Diverse Effects of the NTCP p.Ser267Phe Variant on Disease Progression During Chronic HBV Infection and on HBV preS1 Variability. Front Cell Infect Microbiol, 2019. 9: p. 18.
18.    Keitel, V., et al., Expression and localization of hepatobiliary transport proteins in progressive familial intrahepatic cholestasis. Hepatology, 2005. 41(5): p. 1160-72.
19.    Stieger, B., The role of the sodium-taurocholate cotransporting polypeptide (NTCP) and of the bile salt export pump (BSEP) in physiology and pathophysiology of bile formation. Handb Exp Pharmacol, 2011(201): p. 205-59.
20.    Yan, H., et al., Sodium taurocholate cotransporting polypeptide is a functional receptor for human hepatitis B and D virus. Elife, 2012. 1: p. e00049.
21.    Li, N., et al., Association of genetic variation of sodium taurocholate cotransporting polypeptide with chronic hepatitis B virus infection. Genet Test Mol Biomarkers, 2014. 18(6): p. 425-9.
22.    Bogomolov, P., et al., Treatment of chronic hepatitis D with the entry inhibitor myrcludex B: First results of a phase Ib/IIa study. J Hepatol, 2016. 65(3): p. 490-8.
23.    Li, W. and S. Urban, Entry of hepatitis B and hepatitis D virus into hepatocytes: Basic insights and clinical implications. J Hepatol, 2016. 64(1 Suppl): p. S32-40.
24.    Trauner, M., et al., New therapeutic concepts in bile acid transport and signaling for management of cholestasis. Hepatology, 2017. 65(4): p. 1393-1404.
25.    Eller, C., et al., The functional role of sodium taurocholate cotransporting polypeptide NTCP in the life cycle of hepatitis B, C and D viruses. Cell Mol Life Sci, 2018. 75(21): p. 3895-3905.
26.    Loglio, A., et al., Excellent safety and effectiveness of high-dose myrcludex-B monotherapy administered for 48&#x202f;weeks in HDV-related compensated cirrhosis: A case report of 3 patients. Journal of Hepatology, 2019. 71(4): p. 834-839.
27.    Vildhede, A., et al., Hepatic uptake of atorvastatin: influence of variability in transporter expression on uptake clearance and drug-drug interactions. Drug Metab Dispos, 2014. 42(7): p. 1210-8.