Bile Add Transporters

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. 

S. Stengelin, H. Thuring, W. Kramer, Insights into the bile add transportation system The human deal lipid-binding protein-cholyltaurine complex and its comparison with homologous structures, Proteins Struct., Funct. Genet. 2003, 50, 312-328. 

Oelleers, P-, Kirby, L-, Heubi, J and Dawson, P. (1997). Primary bile acid malabsorption caused by mutations in the ileal sodium-dependent bile add transporter gene (SLCT0A2). . CUn. Invest. 99, 1880-1887. 

The apical localized sodium-dependent bile add transporter (ASBT) is expressed in the human duodenum and ileum and is barely detectable in colon [16]. ASBT transports bile adds such as glycodeoxycholate and chenodeoxycholic add (XX) [49, 50]. Few examples exist where the bile acid scaffold has been used as a promoiety for a prodrug approach. ASBT has micromolar affinities for the natural substrates, and the studies on ASBT are too few to make a general statement on the potential and role of this transporter in drug absorption [49, 50]. 

Wang, W Xue, S Ingles, S.A., Chen, Q Diep, A.T., Frankl, H.D., Stolz, A. and Haile, R.W. (2001) An association between genetic polymorphisms in the ileal sodium-dependent bile add transporter gene and the risk of colorectal adenomas. Cancer Epidemiology, Biomarkers el Prevention, 10 (9), 931-936. 

Several experimental systems to check the inhibition potency of bile add transport have been characterized. Using sandwich-cultured human hepatocytes, bosentan, cyclosporin A, CI-1034 (endothelin-A receptor antagonist), glyburide, erythromycin estolate, and troleandomycin could inhibit the taurocholate efflux to the bile pocket [234]. Moreover, Mita et al. [235] construded NTCP/BSEP double-transfeded cells and some cholestasis-induced compounds inhibited both the NTCP-mediated uptake and the BSEP-mediated efflux of taurocholate. Then, they have found fluorescent bile acids whose transcellular transport was dearly observed, which may be used for the rapid identification of inhibitors of NTCP and BSEP in drug screening process [235]. 

Alrefai, W.A. and Gill, R.K (2007) Bile add transporters structure, function, regulation and pathophysiological implications. Pharmaceutical Research, 24, 1803-1823. 

Chignard, N., Mergey, M., Veissiere, D., Parc, R., Capeau, J., Poupon, R., Paul, A., and Housset, C. (2001) Bile add transport and regulating functions in the human biliary epithelium. Hepatology, 33, 496-503. 

Anderberg, E. K., C. Nystrom, and P. Artursson. Epithelial transport of drugs in cell culture. VII Effects of pharmaceutical surfactant excipients and bile adds on transepithelial permeability in monolayers of human intestinal epithelial (Caco-2) cells,... 

Hidalgo, I. J., Borchardt, R. T., Transport of bile adds in a human intestinal epithelial cell line, Caco-2, Biochim. Biophys. Acta 1990, 1035, 97— 103. 

Sandker, G. W., Weert, B., Olinga, P., Wolters, H., Slooff, M. J., Meijer, D. K., Groothuis, G. M., Characterization of transport in isolated human hepatocytes. A study with the bile add taurocholic add, the uncharged ouabain and the organic... 

Pagels, P., Starke, D., Kramer, W., Hepatobiliary transport of bile add amino add, bile add peptide, and bile acid oligonucleotide conjugates in rats, Hepatology 1999, 30, 1257-1268. 

PXR CAR FXR LXR AhR 3A4 and others 2B, 2C, 3A4 7A 7A 1A1, 1A2, 1A6, 1B1, 2S1 Xenobiotic metabolism regulation, antioxidant Xenobiotic metabolism regulation Bile add metabolism and transport Reverse cholesterol transport and absorption Reproduction and development regulation... 

Figure 4.13 Uptake of bile acids in the jejunum. Bile adds (BA) and cholesterol (C) are secreted from the liver, via the bile, into the duodenum. Cholesterol is transported back into the blood, from the enterocyte, within chylomicrons. The latter enter the lymphatic system (i.e. the lacteals). Bile acids are absorbed from the jejunum into the hepatic portal vein for re-uptake into the liver.

Figure 2.3 Absorption of bile acids by the cholangiocyte in the cholehepatic shunt. Bile acids are absorbed at the apical membrane of the cholangioc5de by the apical sodium-dependent bile-acid transporter (ASBT) that causes cholehepatic shunting of bile acids back to the hepatocyte. Absorbed bile adds are exported across the basolateral membrane by multi-drug-resistance-associated protein 3 (MRP3), a truncated form of ASBT or by the het-eromeric organic solute (OST) a and p forms. Bile adds cause choleresis that is rich in bicarbonate ions secreted by the chloride/bicarbonate ion exchanger.

Bile acids are recycled via the enterohepatic circulation, with less than 5% of the total bile acid pool entering the colon.Bile adds are reabsorbed by ileum columnar epithelium cells and are transported back to the liver by the portal vein where they are extracted by hepatocytes. Approximately 6-12 enterohepatic circulations occur daily. Free bile acids, like DCA, are partly absorbed into the colon and enter the enterohepatic circulation, where they are... 

Mita, S. et al. (2006) Inhibition ofbile add transport across Na + /taurocholate cotransporting polypeptide (SLClOAl) and bile salt export pump (ABCB 11)-coexpressing LLC-PKl cells by cholestasis-inducing drugs. Drug Metabolism and Disposition The Biological Fate of Chemicals, 34 (9), 1575-1581. 

The bile add-independent fraction (200 ml) is to be found in the absence or near absence of bile acids. This fraction is formed chiefly in the perivenous acinus, (s. tab. 3.2) However, Na /K -ATPase, glutathione and an active bicarbonate transporter also play an important role. Likewise, the prostaglandins Ai, E and E2 stimulate the production of this fraction. 

Kouzuki et al. [157, 158] have proposed a method using reference compounds to determine the contribution of rat Oatplal and Ntcp to the hepatic uptake of bile adds and organic anions. This concept is originally established in the field of metabolic enzymes by Crespi et al. [159] and they named it relative adivity fador (RAF) method. In this method, they checked the transport activity of both test compounds and the reference compounds, which should be specific substrates for single transporters, in short-term cultured rat hepatocytes and transporter-expressing COS-7 cells. Then, they estimated the contribution from the following equations ... 

Bodo, A., Bakos. E.. Szeri. F., Varadi, A, and Sarkadi, B. (2003) Differential modulation of the human liver conjugate transporters MRP2 and MRP3 by bile adds and organic anions. The Journal of Biological Chemistry. 278 (26). 23529-23537. 

When transfected in cultured epithelial cells, it mediates not only the apical transport of methotrexate and folate but also that of taurocholate and prostaglandin E2. In Hs-inhibition studies, steroids, bile add analogs, and cardiac glycosides were shown to have a high affinity for OAT-K2, suggesting that it participates to the apical transport of hydrophobic anionic compounds in the kidney [52]. 

During this biological recycling of bile acids in the enterohepatic circulation, the bile add (1.5 to 4g) is circulated 6 to 15 times per day, suggesting high overall transport capacity of the transport system for bile acids in the liver and the small intestine. 

Bile acids are the end products of hepatic cholesterol catabolism and play essential roles in eliminating cholesterol from the body. However, pathophysiological accumulation of bile acids elicits cytotoxicity and can lead to cholestasis in livers. PXR plays a critical role in bile acid detoxification, by regulating bile add biosynthesis, transport and metaboUsm. Stndies in PXR knock out and humanized PXR mice revealed that PXR reduces secondary bile acid lithocholic add (LCA)-induced liver toxidty [77], PXR regulates... 

Elkins, C.A. and Savage, D.C. (2003) CbsT2 from Lactobacillus johnsonii 100-100 is a transport protein of the major facilitator superfamily that facOitates bile add antiporL J Mol Microbiol Biotechnol 6, 76-87. 

In the search for bUe-add resorption inhibitors (BARI), a predictive 3-D-QSAR pharmacophore model for the deal Na+/bile acid cotransporter was derived, which enhanced the understanding of binding and transport properties [205]. This model was then also successfully explored to search for potential substitution sites, which are not relevant for the SAR of this series, while they allow the addition of additional substituents to minimize the oral uptake of inhibitors. 

---