Ileal bile acid transporter

Root, C., et al. Ileal bile acid transporter inhibition, CYP7A1 induction, and antilipemic action of 264W94. 

Annaba F, Sarwar Z, Kumar P, Saksena S, Turner JR, Dudeja PK, Gill RK, Alrefai WA (2007) Modulation of ileal bile acid transporter (ASBT) activity by depletion of plasma membrane cholesterol association with lipid rafts. Am J Physiol Gastrointest Liver Physiol 294 489-497... 

Utility Ileal Bile Acid Transporter for Lowering Blood Serum Cholesterol... 

It is clear that the presence of bile salts in the G1 tract can alter drug ab-sorptiou iu mauy different ways. Bile salts may increase the total solubility of the drug compouud iu the GI lumen, possibly decrease the free concentration of the drug by micellar encapsulation or modulate the trausport characteristics of compouuds that are actively transported by the ileal bile acid transporter or by other transporters, such as P-gp (Ingels et al., 2002). 

The ileal bile acid transporter (IBAT) transports conjugated bile acids in a Na + -dependent manner. Like the peptide transporter, it serves as a target for prodrugs, which consist of drugs being coupled to the hydroxyl group at position 3 of the steroid ring system of a bile acid [25, 26]. 

Neimark, E., Chen, F., Li, X., and Shneider, B. L. (2004) Bile acid-induced negative feedback regulation of the human ileal bile acid transporter. Hepatology 40, 149-156. 

Jung, D., Fantin, A. C., Scheurer, U., Fried, M., and Kullak-Ublick, G. A. (2004) Human ileal bile acid transporter gene ASBT (SLC10A2) is transactivated by the glucocorticoid receptor. Gut 53, 78-84. 

In the intestine the ileal bile acid transporter (IBAT) imports bile acids from the lumen into intestinal epithelial cells (step 2]). IBAT is a Na -linked symporter (see Figure 7-21) that uses the energy released by the movement of Na down its concentration gradient to power the uptake of about 95 percent of the bile acids. Those bile acids Imported on the apical side of intestinal epithelial cells move intracellularly with the aid of intestinal bile acid-binding protein (I-BABP) to the basolateral side. There, they are exported into the blood by poorly characterized transport proteins (step 3]) and eventually returned to liver cells by another Na -linked... 

Dawson, P.A., Haywood, J., Craddock, A.L., Wilson, M., Tietjen, M., Kluckman, K., Maeda, N., Parks, J.S. 2003. Targeted deletion of the ileal bile acid transporter eliminates enterohepatic cycling of bile acids in mice. J. Biol. Chem. 278 33920-339207. 

Sun, A. Q. SaUcar, R. Sachchidanand, S. Xu, S. Zeng, L. Zhou, M. M. Suchy, F. J. 2003. A 14-amino acid sequence with a beta-turn structure is required for apical membrane sorting of the rat ileal bile acid transporter. J. Biol Chem. 278 4000-4009. 

K. Bock, H. Kleine, G. Neckermann, A. Hoffmann, C. Pittius, E. Falk, H. W. Fehlhaber, H. Kogler, and M. Friedrich, J. Med. Chem., 37, 873 (1994). Specific Inhibitors Of Ileal Bile Acid Transport. 

Shneider, B. L., et al. Cloning and molecular characterization of the ontogeny of a rat ileal sodium-dependent bile acid transporter. J. 

Wong, M. H., P. Oelkers, and P. A. Dawson. Identification of a mutation in the ileal sodium-dependent bile acid transporter gene that abolishes transport activity. J. Biol. Chem. 1995, 270, 27228-27234. 

Oelkers, P., et al. Primary bile acid malabsorption caused by mutations in the ileal sodium-dependent bile acid transporter gene (SLC10A2). J. Clin. Invest. 1997, 99, 1880-1887. 

Wess, G., Kramer, W., Han, X. B., Bock, K., Enhsen, A., Glombik, H., Baringhaus, K. H., Boger, G., Urmann, M., Hoffmann, A. et al., Synthesis and biological activity of bile acid-derived HMG-CoA reductase inhibitors. The role of 21-methyl in recognition of HMG-CoA reductase and the ileal bile add transport system, /. Med. Chem. 1994, 37, 3240-3246. 

Buhman, K. K., Furumoto, E. J., Donkin, S. S., and Story, J. A. (2000). Dietary psyllium increased expression of ileal apical sodium-dependent bile acid transporter mRNA coordinately with dose-responsive changes in bile acid metabolism in rats. J. Nutr. 130, 2137-2142. 

Secondly, ileal resection disrupts enterohepatic circulation of bile acids due to loss of the ileal sodium-dependent bile acid transporter (ISBT) leading to... 

W. Wang, S. Xue, S. A. Ingles, Q. Chen, A. T. Diep, H. D. Frankl, A. Stolz and R. W. Haile, An association between genetic polymorphisms in the ileal sodium-dependent bile-acid transporter gene and the risk of colorectal adenomas, Cancer Epidemiol. Biomarkers Prev., 2001, 10, 931. 

Dawson PA, Hubbert M, Haywood J, et al. The heteromeric organic solute transporter alpha-beta, Ostalpha-Ostbeta, is an ileal basolateral bile acid transporter. J Biol Chem 2005 280 6960-6968. 

Craddock AL, Love MW, Daniel RW et al. (1998) Expression and transport properties of the human ileal and renal sodium-dependent bile acid transporter. Am J Physiol 274(1 Pt 1) G157-G169... 

Wong MH, Rao PN, Pettenati MJ, Dawson PA (1996) Localization of the ileal sodium-bile acid transporter gene (SLC10A2) to human chromosome 13q33. Genomics 33 536-540... 

Kurz, M., Brachvogel, V., Matter, H., Stenge-lin, S., Thuring, H., and Hamer, W. (2003) Insights into the bile acid transportation system the human ileal lipid-binding pro-tein-cholyltaurine complex and its comparison with homologous structures. Proteins 50, 312-328. 

Figure 8.9. Physiology and molecular biology of intestinal bile acid transport. Bile acids are actively absorbed in enterocytes through a sodium-dependent cotransporter, ASBT. The sodium gradient is maintained by the sodium-potassium ATPase, located at the basolateral membrane. In the ( osol, bile acids are shuttled through the cell by the aid of various proteins, most importantly the ileal hille acid binding protein, iBABP. An anion exchanger transports bile acids across the basolateral membrane into the portal circulation.

The first such inhibitors consisted of the coupling of two bile acid molecules by means of a spacer to allow simultaneous interaction with more than one transporter site, resulting in an efficient inhibition of bile acid reabsorption without or with only low absorption of the inhibitor itself (110) (Fig. 8.13). Recently, it was shown that a benzothiazepine derivative, 2164U90, was able to selectively inhibit active ileal bile acid absorption in rats, mice, mon-... 

Some recent studies on vitamin transport using membrane vesicles include those of vitamin B6 by rat kidney brush border membranes (Bowman et al, 1990), ascorbic acid by teleost intestinal brush border membranes (Mafha et ai, 1993), biotin by human kidney brush border membranes (Baur and Baumgartner, 1992), pantothenate by human placental brush border membranes (Grassl, 1992), folate and riboflavin by rabbit intestinal brush border membranes (Said and Mohammadkhani, 1993a,b Said et al, 1993), and thiamine by rat small intestine basolateral membranes (Laforenza et al, 1993). Bile acid transport in human placental, rat ileal, and rabbit small intestinal brush border membrane vesicles (Dumaswala et al, 1993 Gong et al, 1991 Kramer et al, 1993) and the effect of vitamin D status... 

In a structure activity investigation, the following structural elements necessary for the molecular recognition of a bile acid by the ileal Na /bile acid transport system were identified [21,22] ... 

The chlorambucil-bile acid conjugate inhibited the uptake of Na" "-dependent taurochorate into both the liver and the intestinal membranes in a concentration-dependent manner [24]. Kullak-Ublick et al. [25] demonstrated that a chlorambucil-taurocholic acid conjugate was transported by the bile acid transporter in cRNA-injected oocytes. Furthermore, the liver-selectivity of HMG-CoA reductase inhibitors conjugated to bile acids have been investigated [26,27]. The Na -dependent uptake of taurocholate into rat hepatocytes and into rat ileal brush border membrane vesicles was found to be inhibited by the bile acid prodrugs of HMG-CoA reductase inhibitors in a concentration-dependent manner. Bile acid-prodrugs, which... 

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