Sodium taurocholate cotransporting polypeptide (NTCP) deficiency is an inborn error of bile acid metabolism caused by mutations of SLC10A1 gene. This paper reports the clinical and genetic features of a patient with this disease. A 3.3-month-old male infant was referred to the hospital with the complaint of jaundiced skin and sclera over 3 months. Physical examination revealed moderate jaundice of the skin and sclera. The liver was palpable 3.5 cm below the right subcostal margin with a medium texture. Serum biochemistry analysis revealed markedly elevated bilirubin (predominantly direct bilirubin) and total bile acids (TBA), as well as decreased 25-OH-VitD level. On pathological analysis of the biopsied liver tissue, hepatocyte ballooning and cholestatic multinucleate giant cells were noted. The lobular architecture was distorted. Infiltration of inflammatory cells, predominantly lymphocytes, was seen in the portal tracts. In response to the anti-inflammatory and liver protective drugs as well as fat-soluble vitamins over 2 months, the bilirubin and transaminases levels were improved markedly while the TBA kept elevated. Because of persisting hypercholanemia on the follow-up, SLC10A1 gene analysis was performed at his age of 17.2 months. The child proved to be a homozygote of the reportedly pathogenic variant c.800C>T (p. Ser267Phe), while the parents were both carriers. NTCP deficiency was thus diagnosed. The infant was followed up until 34.3 months old. He developed well in terms of the anthropometric indices and neurobehavioral milestones. The jaundice disappeared completely. The liver size, texture and function indices all recovered. However, the hypercholanemia persisted, and the long-term outcome needs to be observed.
Humans ; Infant ; Male ; Organic Anion Transporters, Sodium-Dependent ; deficiency ; genetics ; Symporters ; deficiency ; genetics

Sodium taurocholate cotransporting polypeptide (NTCP) deficiency is caused by SLC10A1 mutations impairing the NTCP function to uptake plasma bile salts into the hepatocyte. Thus far, patients with NTCP deficiency were rarely reported. The patient in this paper was a 5-month-19-day male infant with the complaint of jaundiced skin and sclera for 5.5 months as well as abnormal liver function revealed over 4 months. His jaundice was noticed on the second day after birth, and remained visible till his age of 1 month and 13 days, when a liver function test unveiled markedly elevated total, direct and indirect bilirubin as well as total bile acids (TBA). Cholestatic liver disease was thus diagnosed. Due to unsatisfactory response to medical treatment, the patient underwent exploratory laparotomy, cholecystostomy and cholangiography when aged 2 months. This revealed inspissated bile but unobstructed bile ducts. Thereafter, his jaundice subsided, but the aminotransferases and TBA levels gradually rose. Of note, his mother also had mildly elevated plasma TBA. Since the etiology was unclear, no specific medication was introduced. The infant has been followed up over 2 years. The aminotransferases recovered gradually, but TBA levels fluctuated within 23.3-277.7 μmol/L (reference range: 0-10 μmol/L). On SLC10A1 genetic analysis at 2 years and 9 months, both the infant and his mother proved to be homozygous for a pathogenic variant c.800C>T(p.S267F), and NTCP deficiency was thus definitely diagnosed. The findings suggest that, although only mildly increased plasma TBA is presented in adults with NTCP deficiency, pediatric patients with this disorder exhibit persistent and remarkable hypercholanemia, and some patients might manifest as cholestatic jaundice in early infancy.
Humans ; Infant ; Jaundice, Obstructive ; etiology ; Male ; Organic Anion Transporters, Sodium-Dependent ; blood ; deficiency ; genetics ; Symporters ; blood ; deficiency ; genetics

Liver is regarded as one of the most important organs for drug clearance in the body, which mediates both the metabolism and biliary excretion of drugs. Transporters are a class of functional membrane proteins and control the movement of substances into or out of cells. Transporters, which are extensively expressed in the liver, play important roles in the drug hepatic disposition by regulating the uptake of drugs from blood into hepatocytes or the efflux of drugs and their metabolites into bile. In this review, the localization, functions and substrate selectivity of the major transporters in the liver will be summarized, and the impacts of these transporters on drug hepatic disposition, the potential drug-drug interactions as well as their genetic polymorphisms will also be reviewed.
ATP Binding Cassette Transporter, Sub-Family G, Member 2 ; ATP-Binding Cassette Transporters ; genetics ; metabolism ; ATP-Binding Cassette, Sub-Family B, Member 1 ; genetics ; metabolism ; Bile ; metabolism ; Biological Transport ; Drug Interactions ; Humans ; Liver ; metabolism ; Membrane Transport Proteins ; genetics ; metabolism ; Metabolic Clearance Rate ; Multidrug Resistance-Associated Proteins ; genetics ; metabolism ; Neoplasm Proteins ; genetics ; metabolism ; Organic Anion Transporters ; genetics ; metabolism ; Organic Anion Transporters, Sodium-Dependent ; metabolism ; Organic Anion Transporters, Sodium-Independent ; genetics ; metabolism ; Organic Cation Transport Proteins ; genetics ; metabolism ; Pharmacokinetics ; Polymorphism, Genetic ; Symporters ; metabolism

ATP Binding Cassette Subfamily B Member 11 ; ATP Binding Cassette Transporter, Sub-Family G, Member 2 ; ATP-Binding Cassette Transporters ; physiology ; ATP-Binding Cassette, Sub-Family B, Member 1 ; physiology ; Animals ; Bile ; metabolism ; Biliary Tract ; physiology ; Drug Interactions ; Drug Resistance, Multiple ; Humans ; Liver ; physiology ; Multidrug Resistance-Associated Proteins ; physiology ; Neoplasm Proteins ; physiology ; Organic Anion Transporters ; physiology ; Organic Anion Transporters, Sodium-Dependent ; physiology ; Organic Cation Transport Proteins ; physiology ; Symporters ; physiology

NTCP is specifically expressed on the basolateral membrane of hepatocytes, participating in the enterohepatic circulation of bile salts, especially conjugated bile salts, to maintain bile salts homeostasis. In addition, recent studies have found that NTCP is a functional receptor of HBV and HDV. Therefore, it is important to study the interaction between drugs and NTCP and identify the inhibitors/substrates of NTCP. In the present study, a LLC-PK1 cell model stably expressing human NTCP was established, which was simple and suitable for high throughput screening, and utilized to screen and verify the potential inhibitors of NTCP from 102 herbal medicinal ingredients. The results showed that ginkgolic acid (GA) (13 : 0), GA (15 : 1), GA (17 : 1), erythrosine B, silibinin, and emodin have inhibitory effects on NTCP uptake of TCNa in a concentration-dependent manner. Among them, GA (13 : 0) and GA (15 : 1) exhibited the stronger inhibitory effects, with IC50 values being less than 8.3 and 13.5 μmol·L(-1), respectively, than the classical inhibitor, cyclosporin A (CsA) (IC50 = 20.33 μmol·L(-1)). Further research demonstrated that GA (13 : 0), GA (15 : 1), GA (17 : 1), silibinin, and emodin were not substrates of NTCP. These findings might contribute to a better understanding of the disposition of the herbal ingredients in vivo, especially in biliary excretion.
Animals ; Drug Evaluation, Preclinical ; Humans ; Kinetics ; LLC-PK1 Cells ; Models, Biological ; Organic Anion Transporters, Sodium-Dependent ; antagonists & inhibitors ; chemistry ; metabolism ; Plant Extracts ; chemistry ; pharmacology ; Plants, Medicinal ; chemistry ; Structure-Activity Relationship ; Swine ; Symporters ; antagonists & inhibitors ; chemistry ; metabolism

OBJECTIVE: To determine whether SC-435, a new ileal apical sodium-codependent bile acid transporter (IBAT) inhibitor, can alter the gastrointestinal motility in guinea pigs. METHODS: Sixty guinea pigs received regular diet or IBAT inhibitor (SC-435) diet for 2, 4, and 8 weeks, respectively. At the end of the feeding period, the gallbladder motility was assessed and then four bipolar silver electrodes were implanted on the antrum, duodenum, jejunum, and ileum. Seven days later, migrating motor complex (MMC) was recorded and the total bile acid pool size was measured according to the isotope dilution principle in the meantime. RESULTS: After feeding SC435, the gallbladder motility was declined in the 4-week group and the 8-week group. The bile acid pool size decreased by 17.11% (P <0.05) in the 4-week group and 48.35% (P < 0.05) in the 8-week group. The places of origin of MMC were changed where antral origins (37%) and duodenal origins (46%) decreased whereas jejunal origins (17%) increased. The MMC cycle period was prolonged in the duodenum (1.16 times in the 4-week group, P < 0.05; 1.38 times in the 8-week group, P < 0.05) whereas MMC amplitude fell in the duodenum (10.58% in the 4-week group, P <0.05; 49.17% in the 8-week group, P <0.05). There were not significant differences in all parameters of MMC between the control group and the 2-week group in guinea pigs. CONCLUSION The IBAT inhibitor (SC-435) reduces the bile acid pool size and inhibits the MMC cycle activity. MMC is related to the enterohepatic circulation of bile acids, which is consistent with the changes of the bile acid pool size in guinea pigs.
Animals ; Bile Acids and Salts ; Cyclic N-Oxides ; pharmacology ; Female ; Gallbladder ; physiology ; Gastrointestinal Motility ; drug effects ; physiology ; Guinea Pigs ; Myoelectric Complex, Migrating ; drug effects ; Organic Anion Transporters, Sodium-Dependent ; antagonists & inhibitors ; Random Allocation ; Symporters ; antagonists & inhibitors ; Tropanes ; pharmacology

Hepatitis B virus (HBV) is the prototype of hepatotropic DNA viruses (hepadnaviruses) infecting a wide range of human and non-human hosts. Previous studies with duck hepatitis B virus (DHBV) identified duck carboxypeptidase D (dCPD) as a host specific binding partner for full-length large envelope protein, and p120 as a binding partner for several truncated versions of the large envelope protein. p120 is the P protein of duck glycine decarboxylase (dGLDC) with restricted expression in DHBV infectible tissues. Several lines of evidence suggest the importance of dCPD, and especially p120, in productive DHBV infection, although neither dCPD nor p120 cDNA could confer susceptibility to DHBV infection in any cell line. Recently, sodium taurocholate cotransporting polypeptide (NTCP) has been identified as a binding partner for the N-terminus of HBV large envelope protein. Importantly, knock down and reconstitution experiments unequivocally demonstrated that NTCP is both necessary and sufficient for in vitro infection by HBV and hepatitis delta virus (HDV), an RNA virus using HBV envelope proteins for its transmission. What remains unclear is whether NTCP is the major HBV receptor in vivo. The fact that some HBV patients are homozygous with an NTCP mutation known to abolish its receptor function suggests the existence of NTCP-independent pathways of HBV entry. Also, NTCP very likely mediates just one step of the HBV entry process, with additional co-factors for productive HBV infection still to be discovered. NTCP offers a novel therapeutic target for the control of chronic HBV infection.
Animals ; Carboxypeptidases/genetics/*metabolism ; Gene Products, pol/genetics/metabolism ; Heparan Sulfate Proteoglycans/metabolism ; Hepatitis B virus/*physiology ; Hepatocytes/metabolism/virology ; Organic Anion Transporters, Sodium-Dependent/antagonists & inhibitors/genetics/metabolism ; RNA Interference ; Symporters/antagonists & inhibitors/genetics/metabolism ; Viral Envelope Proteins/metabolism ; Virus Internalization

With recent advances in molecular and genomic investigations, the impact of hepatitis B viral and host factors on the progression of chronic HBV infection has been explored. For viral factors, hepatitis B viral load is a strong predictor for liver disease progression. Hepatitis B viral kinetics appear to be important for successful anti-viral therapy. Serum HBsAg level serves as a complementary marker to viral load for the prediction of HBV-related adverse outcomes in patients with low viral load. In those with low viral load, high serum HBsAg level is associated with higher risks of cirrhosis and HCC. Hepatitis B core-related antigen (HBcrAg) induces host immune responses, and the reduction of the HBcrAg level as well as the increment of total anti-HBc level are significantly associated with favorable outcomes. HBV genotypes (genotype C/D) and mutants (basal core promoter and deletion mutation in pre-S genes) are well known viral genetic markers to predict disease progression. For host factors, serum inflammatory biomarkers have been developed to evaluate the HBV-associated hepatic necroinflammation and fibrosis. Host single nucleotide polymorphism on sodium taurocholate cotransporting polypeptide (NTCP, an HBV entry receptor) may be associated with a decreased risk for cirrhosis and HCC. In conclusion, patients with chronic hepatitis B should be evaluated with relevant viral and host markers to identify those who are at a higher risk of liver disease progression and then receive timely antiviral therapy.
Biomarkers/*blood ; DNA, Viral/blood ; Hepatitis B Surface Antigens/blood ; Hepatitis B e Antigens/blood ; Hepatitis B virus/genetics ; Hepatitis B, Chronic/complications/*diagnosis/prevention & control ; Humans ; Liver Cirrhosis/etiology ; Organic Anion Transporters, Sodium-Dependent/genetics ; Polymorphism, Single Nucleotide ; Risk Factors ; Symporters/genetics

BACKGROUND: Vitamin C is one of the most typical types of water-soluble antioxidants that exerts a variety of biochemical actions on a living body. It acts on the skin by promoting wound healing, preventing skin aging, and inhibiting skin cancer. It also works not only as an antioxidant, protecting the skin from UV radiation but also as an anti-inflammatory agent. It reinforces immunity as well. Recent studies proved the whitening effect of vitamin C, and it can be instilled into the skin by way of iontophoresis. When vitamin C is transported in vivo it is either by simple diffusion or by a transporter. Only a small amount is transported by simple diffusion and the transporter is responsible for most of the vitamin C transport. This study was designed to evaluate the presence of sodium dependent vitamin C transporter (SVCT) and to identify which factor controls its expression. METHODS: Expressions of SVCT 1 and 2 mRNA in the rats' dermal fibroblast were measured by RT-PCR at 3, 6, 12, 24, and 48 hours. RESULTS: The results were used to compare the expression levels of SVCT-1 and SVCT-2 when treated with TGF-beta, estradiol, and retinoic acid. Estradiol showed the highest level of expression of SVCT-1 and SVCT-2. The next highest was TGF-beta, followed by retinoic acid. CONCLUSION: SVCT-1 and SVCT-2 were found to be expressed in the rats' dermal fibroblasts, and exposure to estradiol, TGF-beta and retinoic acid resulted in a higher degree of their expression.
Animals ; Antioxidants ; Ascorbic Acid ; Diffusion ; Estradiol ; Fibroblasts* ; Iontophoresis ; Rats* ; RNA, Messenger ; Skin ; Skin Aging ; Skin Neoplasms ; Sodium-Coupled Vitamin C Transporters* ; Transforming Growth Factor beta ; Tretinoin ; Wound Healing

Vitamin C is an essential micronutrient that affects immune responses. T cells are one of the main players in acquired immunity and have been reported to be influenced by in vivo vitamin C supplementation. Yet, the way by which T cells uptake vitamin C and what direct effects vitamin C exerts on the cells are not known. To elucidate, we isolated human peripheral blood T cells and analyzed the expression of sodium-dependent vitamin C transporters (SVCT). T cells were activated in vitro in the absence or presence of vitamin C, before or after activation. As results, human T cells expressed SVCT2, but not SVCT1, and the expression level increased following activation. Vitamin C added in the culture media generally did not affect T-cell behaviors following activation, such as proliferation, apoptosis, expression of CD25 and CD69, and interleukin 2 secretion, regardless whether it was added before or after activation. However, exceptionally, high concentration vitamin C, when it was added before activation, but not after activation, did exert toxic effects on cell activation with respect to the above-mentioned parameters. In conclusion, we showed the expression of SVCT2 in human T cells for the first time. Vitamin C exerted toxic effects, at least in vitro, when the concentration was high and when it was given before activation. These toxic effects are not thought to be via anti-oxidant effects of vitamin C.
Adaptive Immunity ; Antioxidants ; Apoptosis ; Ascorbic Acid* ; Culture Media ; Humans* ; In Vitro Techniques* ; Interleukin-2 ; Micronutrients ; Sodium-Coupled Vitamin C Transporters* ; T-Lymphocytes* ; Vitamins*