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

<p>OBJECTIVETo study the effect of Zhusha Anshen pill, cinnabar, HgS, HgCl2 and MeHg on the gene expression of renal transporters in mice.p><p>METHODHealthy male mice were given equivalent physiological saline, Zhusha Anshen pill (1.8 g · kg(-1), containing 0.17 g · kg(-1) of mercury), cinnabar (0.2 g · kg(-1), containing 1.7 g · kg(-1) of mercury), high dose cinnabar (2 g · kg(-1), containing 1.7 g · kg(-1) of mercury), HgS (0.2 g · kg(-1), containing 0.17 g · kg(-1) of mercury), HgCl2 (0.032 g · kg(-1), containing 0. 024 g · kg(-1) of mercury), MeHg (0.026 g · kg(-1), containing 0.024 g · kg(-1) of mercury), once daily, for 30 d, measuring body mass gain. 30 days later, the mice were sacrificed. The mercury accumulation in kidneys was detected with atomic fluorescence spectrometer. Expressions of Oat1, Oat2, Oat3, Mrp2, Mrp4, Urat1 were detected with RT-PCR.p><p>RESULTCompared with the normal control group, a significant accumulation of Hg in kidney in HgCl2 and MeHg groups was observed (P <0.05), but these changes were not found in other groups. Compared with normal control group, mRNA expressions of Oat1 and Oat2 were evidently lower in HgCl2 and MeHg groups, but mRNA expressions of Mrp2 were apparently higher in HgCl2 group (P <0.05), mRNA expression of Mrp4 was significant higher in HgCl2 and MeHg groups, and mRNA expression of Urat1 was apparently lower in MeHg group.p><p>CONCLUSIONHgCl2 and MeHg groups show significant difference from the normal group in mercury accumulation in kidneys and gene expression of kidney transporters, but with no difference between other groups and the normal group. Compared with HgCl2 and MeHg, cinnabar and its compounds could cause lower renal toxicity to mice.p>
Animals ; Carrier Proteins ; genetics ; Drugs, Chinese Herbal ; toxicity ; Gene Expression ; drug effects ; Kidney ; drug effects ; metabolism ; Male ; Mercuric Chloride ; toxicity ; Mercury Compounds ; toxicity ; Methylmercury Compounds ; toxicity ; Mice ; Multidrug Resistance-Associated Proteins ; genetics ; Organic Anion Transport Protein 1 ; genetics ; Organic Anion Transporters, Sodium-Independent ; genetics

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

Renal handling of uric acid mainly occurs in the proximal tubule, and bidirectional transport of urate may involve apical absorption via the urate-anion exchanger (URAT1) and basolateral uptake via organic anion transporters (OAT1 and OAT3). In rat kidneys, we investigated whether the protein abundance of URAT1, OAT1, and OAT3 is affected by the increase in uric acid intake. Male Sprague-Dawley rats were randomly divided into control and uric acid-supplemented groups, and uric acid-supplemented rats were given 0.75 g of uric acid per 180 g body weight per day for 8 days. After the animal experiment, kidneys were harvested and semi-quantitative immunoblotting was carried out from cortical homogenates using polyclonal peptide-derived antibodies to URAT1, OAT1, and OAT3. Serum uric acid level showed an increasing tendency (p=0.055) in the uric acid-supplemented rats (2.60+/- 0.27 mg/dL) compared with control rats (1.97+/-0.29 mg/dL), whereas urinary uric acid excretion was not significantly different between the uric acid-supplemented rats (3.27+/-0.40 mg/d) and control rats (2.61+/-0.34 mg/d). URAT1 protein abundance in cortical homogenates was not significantly different between the uric acid-supplemented rats (132+/-14%) and control rats (100+/-7%). However, OAT1 protein abundance was significantly (p<0.05) increased in the uric acid-supplemented rats (148+/-13%) compared with the control rats (100+/-8%). OAT3 protein abundance was not significantly different between the uric acid-supplemented rats (131+/-12%) and control rats (100+/-17%). In conclusion, OAT1 may have a regulatory role in response to the increase in uric acid intake in the rat kidney. The up-regulation of OAT1 would exert stimulation of urinary uric acid excretion and might contribute to protection from hyperuricemia.
Absorption ; Animal Experimentation ; Animals ; Antibodies ; Body Weight ; Humans ; Hyperuricemia ; Immunoblotting ; Kidney* ; Male ; Organic Anion Transport Protein 1 ; Organic Anion Transporters ; Rats* ; Rats, Sprague-Dawley ; Up-Regulation ; Uric Acid*

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

A significant number of organic carboxylic acids have been shown to influence the absorption and distribution of drugs mediated by organic anion transporters (OATs). In this study, uptake experiments were performed to assess the inhibitory effects of cinnamic acid, ferulic acid, oleanolic acid, deoxycholic acid, and cynarin on hOAT1, hOAT3, hOATP1B1, and hOATP2B1. After a drug-drug interaction (DDI) investigation, cinnamic acid, ferulic acid, deoxycholic acid, and cynarin were found and validated to inhibit hOAT1 in a competitive manner, and deoxycholic acid was found to be an inhibitor of all four transporters. The apparent 50% inhibitory concentrations of cinnamic acid, ferulic acid, deoxycholic acid, and cynarin were estimated to be 133.87, 3.69, 90.03 and 6.03 μmol·L(-1) for hOAT1, respectively. The apparent 50% inhibitory concentrations of deoxycholic acid were estimated to be 9.57 μmol·L(-1) for hOAT3, 70.54 μmol·L(-1) for hOATP1B1, and 168.27 μmol·L(-1) for hOATP2B1. Because cinnamic acid, ferulic acid, and cynarin are ingredients of food or food additives, the present study suggests there are new food-drug interactions to be disclosed. In addition, deoxycholic acid may be used as a probe for studying the correlation of OATs and OATPs.
Carboxylic Acids ; pharmacology ; Cinnamates ; pharmacology ; Coumaric Acids ; pharmacology ; Deoxycholic Acid ; pharmacology ; Diet ; Drug Interactions ; HEK293 Cells ; Humans ; Organic Anion Transport Protein 1 ; antagonists & inhibitors ; Organic Anion Transporters ; antagonists & inhibitors ; Plant Extracts ; pharmacology ; Plants, Medicinal ; chemistry

Organic Anion Transporters

The kidney is an important organ for controlling the volume of body fluids, electrolytic balance and excretion/reabsorption of endogenous and exogenous compounds. Among these renal functions, excretion/reabsorption of endogenous and exogenous substance is very important for the maintenance of physiological homeostasis in the body. Recently discovered organic anion transporters (OAT or SLC22A) have important roles for renal functions. It is well known as drug transporter. Several isoforms belong to SLC22A family. They showed different transport substrate spectrums and different localizations within the kidney. Their gene expressions are changed by some stimulus. The functional transport properties are regulated by protein kinase C. In addition, the function of organic anion transporters are also regulated by protein-protein interaction, such as caveolin which is compositional protein of caveolae structure. In this review, we will give an introduction of organic anion transporters and its regulatory mechanisms.
Body Fluids ; Caveolae ; Caveolins* ; Gene Expression ; Homeostasis ; Humans ; Kidney ; Multidrug Resistance-Associated Proteins ; Organic Anion Transporters* ; Protein Isoforms ; Protein Kinase C ; Xenobiotics

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