Role of the intestinal bile acid transporters in bile acid and drug disposition

Abstract

Membrane transporters expressed by the hepatocyte and enterocyte play critical roles in maintaining the enterohepatic circulation of bile acids, an effective recycling and conservation mechanism that largely restricts these potentially cytotoxic detergents to the intestinal and hepatobiliary compartments. In doing so, the hepatic and enterocyte transport systems ensure a continuous supply of bile acids to be used repeatedly during the digestion of multiple meals throughout the day. Absorption of bile acids from the intestinal lumen and export into the portal circulation is mediated by a series of transporters expressed on the enterocyte apical and basolateral membranes. The ileal apical sodium-dependent bile acid cotransporter (abbreviated ASBT; gene symbol, SLC10A2) is responsible for the initial uptake of bile acids across the enterocyte brush border membrane. The bile acids are then efficiently shuttled across the cell and exported across the basolateral membrane by the heteromeric Organic Solute Transporter, OSTα-OSTβ. This chapter briefly reviews the tissue expression, physiology, genetics, pathophysiology, and transport properties of the ASBT and OSTα-OSTβ. In addition, the chapter discusses the relationship between the intestinal bile acid transporters and drug metabolism, including development of ASBT inhibitors as novel hypocholesterolemic or hepatoprotective agents, prodrug targeting of the ASBT to increase oral bioavailability, and involvement of the intestinal bile acid transporters in drug absorption and drug-drug interactions.

Figure 1. Enterohepatic circulation of bile acids showing the individual transport proteins in hepatocytes, ileocytes (ileal enterocytes), and renal proximal tubule cells

After their synthesis or reconjugation, taurine and glycine (T/G) conjugated bile acids (BA) are secreted into bile by the canalicular bile salt export pump (BSEP; gene symbol ABCB11). The small amount of bile acids that have been modified by the addition of sulfate or glucuronide (S/U) are secreted by the multidrug resistance-associated protein-2 (MRP2; gene symbol ABCC2), whereas those modified by additional hydroxylation (H) are secreted by P-glycoprotein (MDR1; gene symbol ABCB1A). These divalent (S/G) or tetrahydroxylated (H) bile acids are present in very small quantities under normal physiological conditions, but may accumulate in disease states such as cholestasis. The bile acids are stored in the gallbladder and empty into the intestinal lumen in response to a meal. Bile acids are poorly absorbed in the proximal small intestine, but efficiently taken up by the apical sodium-dependent bile acid transporter (ASBT; gene symbol SLC10A2) in the ileum. The bile acids bind to the ileal lipid binding protein (ILBP; gene symbol FABP6) in the cytosol, and are efficiently exported across the basolateral membrane into the portal circulation by the heteromeric transporter OSTα-OSTβ. The multidrug resistance-associated protein-3 (MRP3; gene symbol ABCC3) is a minor contributor to basolateral export of native bile acids from the enterocyte, but may have a more significant role in export of any modified (glucuronidated or sulfated) bile acids that may be formed. MRP2 may also serve to export modified bile acids, across the apical brush border membrane. While most bile acids are absorbed in the small intestine, colonocytes express very low levels of ASBT and appreciable levels of MRP3 and OSTα-OSTβ; these carriers may serve to absorb a fraction of the unconjugated bile acids from the lumen of the colon. After their absorption from the intestine, bile acids travel back to the liver where that are cleared by the Na+- taurocholate cotransporting polypeptide (NTCP; gene symbol SLC10A1). Members of the Organic Anion Transport Protein family, OATP1B1 (gene symbol SLCO1B1) and OATP1B3 (gene symbol SLCO1B3) also participate, and are particularly important unconjugated bile acids. Under cholestatic conditions, unconjugated, conjugated, or modified bile acids can be effluxed across the basolateral (sinusoidal) membrane of the hepatocyte by OSTα-OSTβ, MRP3, or multidrug resistance-associated protein-4 (MRP4; gene symbol ABBC4) into the systemic circulation. Under normal physiological conditions, a fraction of the bile acid escapes first pass hepatic clearance enters the systemic circulation. The free bile acids are filtered by the renal glomerulus, efficiently reclaimed by the ASBT in the proximal tubules, and exported back into the systemic circulation, thereby minimizes their excretion in the urine. This efficient renal reabsorption occurs even under cholestatic conditions for unconjugated and conjugated bile acids, when serum bile acid concentrations are dramatically elevated. Overall, this integrated transport system minimizes fecal and urinary bile acid loss and functions to largely restrict these potentially cytotoxic detergents to the intestinal and hepatobiliary compartments.

Figure 2. Location of coding region single nucleotide polymorphisms and mutations in the human ileal bile acid transporter gene (SLC10A2)

A schematic diagram depicting the human ASBT protein and gene is shown. The amino acid positions disrupted by the intron/exon junctions are indicated above the schematic of the ASBT protein. The seven predicted transmembrane domains (TM1–TM7) are shown as brown bars. The location of coding region polymorphisms (V98I, V159I, A171S, F296L), and dysfunctional bile acid transporter mutations (C105F, L243P, T262M, M264V, P290S) identified to date is indicated below each exon.