PortaCellTec biosciences GmbH

ASBT (SLC10A2)

Molecular structure and Tissue distribution
The ileal counterpart to the hepatic NTCP is the apical sodium-dependent bile acid transporter ASBT. Asbt was originally cloned from a hamster intestinal cDNA library by expression cloning. Subsequently, human ASBT, rat Asbt, rabbit Asbt, and mouse Asbt were cloned from the ileum. The ASBT/Asbt proteins of all mentioned species consist of 348 amino acids and show an overall amino acid identity of >80%. However, sequence identity to the NTCP is relatively low, at 35%. The human ASBT gene is located on chromosome 13q33. Similar to NTCP/Ntcp, ASBT/Asbt transports conjugated bile acids with high affinity in a sodium-dependent manner. This transport is electrogenic and shows a 2:1 Na+/bile acid coupling stoichiometry. In contrast to the basolateral localisation of Ntcp, Asbt is highly expressed in the apical brush border membrane of enterocytes of the terminal ileum. In the intestine ASBT is thought to be the major route for active bile acid uptake as emphasised by loss-of-function mutations in the human ASBT gene that cause primary bile acid malabsorption, an interruption of the enterohepatic circulation of bile acids, and reduced plasma LDL cholesterol levels. Similarly, genetically engineered knockout mice with a targeted deletion of the Asbt gene (Slc10a2–/–) showed profound intestinal bile acid malabsorption and an increase in faecal bile acid excretion. Further analyses of mRNA and protein expression revealed that Asbt is also expressed in the apical membrane of the renal proximal convoluted tubule, where it might be important for tubular reabsorption of bile acids that are filtrated by the glomeruli. Asbt expression was also detected in the apical membrane of cholangiocytes in the liver bile duct epithelium. The physiological role of Asbt expression in cholangiocytes is not clear.

Interaction of ASBT with endogenous compounds and drugs
The substrate specificity of ASBT was comprehensively examined in several cell systems. ASBT mediate the transport of all physiological dihydroxy and trihydroxy bile acids. The favourite substrates are taurine and glycine conjugates rather than the unconjugated forms of bile acids. Furthermore, affinities and uptake rates for the dihydroxy bile acids (e.g. taurochenodeoxycholate, taurodeoxycholate) were normally higher than for the trihydroxy bile acids (i.e. cholate, taurocholate and glycocholate). ASBT has a lower affinity for the dihydroxy bile acid tauroursodeoxycholate than for taurocholate. ASBT is also very importation in the maintenance of the enterohepatic circulation in the cellular uptake of bile acids in the intestine.
In comparison to NTCP, substrate specificity of ASBT is limited strictly to bile aids. ASBT does not interact with steroid sulfates such as estrone-3-sulfate and DHEA-S, bromosulfophthalein. But ASBT is also involved in transport of several drugs such as dimeric bile acid analogues (e.g. PB3, S 0960), benzothiazepine derivates (e.g. 2164U90, 264W94), benzothiepen derivates (e.g. SC-435) and naphtol derivates (e.g. S8921).

Figure 1 Kinetic of the interaction of taurocholate with hASBT in HEK293 cells
 

PortaCellTec

News

New validated products:

  • mNtcp
  • mOct1

Events

3rd German Pharm-Tox Summit
Göttingen, Germany
26 February - 1 March 2018


Pharmaforum
Saarbrücken, Germany
8 March 2018

 

AAPS Workshop
Virginia, USA
16 - 18 April 2018

 

20th Barrier- and
Transporter-Meeting

Bad Herrenalb, Germany
7 - 9 May 2018

Greifswalder Transporttage 2018
Greifswald, Germany
October 2018

 


Guidance for Industry (FDA and EMA)

Publications