| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
Viewpoint |
–OSTß) Complex: Finding The Missing Link in Enterohepatic Circulation
1 Virginia Commonwealth University School of Pharmacy, Department of Pharmaceutics, Richmond, VA 23298-0533;
2 University of Kentucky Graduate Center for Toxicology, Lexington, KY 40536-0305
SUMMARY
Many drugs are removed from the body through a multistep process that includes covalent conjugation, transport into the bile, and excretion. Bile acids are transported across the ileocyte apical (brush border) membrane by the apical sodium-dependent bile-acid transporter (Asbt), but the identity of the primary transporter responsible for moving bile acids across the basolateral membrane of the ileocyte has remained a mystery, although not for a lack of protein pretenders to the throne. Recent insights from transcriptional profiling studies of wild-type and Asbt-deficient mice indicate that a complex formed by the organic solute carrier proteins 
and ß (Ost and Ostß) is the primary transporter for basolateral bile acid transport.
Biliary excretion is an important route of elimination for many drugs, their conjugates, or both, and some compounds excreted into bile may be reabsorbed in the intestine. Bile acids are excreted and reabsorbed with 
95% efficiency through a process called enterohepatic circulation (1, 2). The occurrence of enterohepatic circulation has long been known, but its mechanisms have only recently been elucidated.
In enterohepatic circulation, bile acids must cross four membranes: the basolateral and apical (canalicular) membranes of both the ileocyte and the hepatocyte. More than 80% of conjugated bile acids are taken up into the liver from portal blood predominantly by the Na+-taurocholate cotransporting polypeptide [NTCP, also termed solute carrier (SLC) 10A1] (3), and uptake of the remainder is mediated by the organic anion transporting polypeptide [OATP, also termed solute carrier Oatp subfamily (SLCO)] family members (2). Alternatively, bile acids can be synthesized de novo exclusively in the hepatocyte. Bile acids are then transported across the canalicular membrane during bile formation by the bile salt export pump [BSEP, also termed ATP-binding cassette (ABC) subfamily B protein 11 (ABCB11)]; bile is secreted into intestinal chyme, and bile acids are reabsorbed into the ileocyte by the apical sodium-dependent bile salt transporter (ASBT, also termed SLC10A2) (2). The mechanism by which efflux across the basolateral membrane from the ileocyte into the portal blood, however, has remained unclear. The likelihood that multidrug resistance–associated protein 3 [MRP3, also termed ABC subfamily C protein 3 (ABCC3)] is the principal basolateral bile acid transporter––responsible for basolateral efflux of bile acids from the ileocyte––was refuted by recent evidence indicating that MRP3 has low affinity for bile acids (4); furthermore, Mrp3 (Box 1
) mRNA expression is relatively low in mouse ileum (5).
| Box 1. Transporter Nomenclature: Roses by Several Names Acronyms that are all capitalized indicate the human form of the protein, whereas acronyms with initial capitals followed by lowercase letters are used for mammalian and other species including the little skate. Both the common and the standard (HUGO) names and acronyms are provided in the text. With the exception of ABCG2 (a standard acronym), common acronyms are used in Figure 1
|
The transcriptional profiling approach used by Dawson et al. has proved effective in identifying the candidate protein(s) responsible for basolateral bile acid transport in the ileocyte (5). They hypothesized that the expression of the transporter would be high in the ileum and would be stimulated by bile acids. Dawson et al. used Slc10a2–/ – mice, deficient in Asbt, anticipating that decreased concentrations of bile acids in ileocytes and increased (10-fold) bile acid flux through the cecum and colon would decrease (in ileocytes) and increase (in cecum and colon) the expression of the basolateral transporter (5). They found that expression of the mouse ortholog of the organic solute transporter alpha (Ost) subunit was greatly increased in the colon of Slc10a2–/ – mice. Interestingly, Ost and Ostß were discovered in a primitive marine vertebrate, the little skate (Leucoraja erinacea), through an expression cloning search for novel Oatps (6).
Dawson et al. showed that in mice, the expression of Ost and Ostß closely parallel each other and that of Asbt, but not that of Mrp3 (5). Ost is composed of 340 amino acids, and is predicted to have seven transmembrane–spanning domains, whereas Ostß has 128 amino acids, and a single transmembrane domain. Their amino acid sequences are not similar to other previously identified solute carrier (SLC) gene family members, indicating that Ost and Ostß form a unique transporter. The authors transiently transfected human embryonic kidney (HEK) 293 cells and stably transfected Madin-Darby canine kidney (MDCK) cells, finding that coexpression of Ost and Ostß is required for mature glycosylation, membrane targeting, and taurocholate transport activity of the complex. The requirement for two distinct proteins from distinct genes is uncommon, but has been compared to the architecture of the heterodimeric Na+-K+–ATPase, in which the -subunit contains ten membrane-spanning domains and provides the transport and catalytic activities, whereas the ß-subunit has only one membrane-spanning domain but is required for pump assembly and targeting to the membrane (6). Furthermore, despite only 25–41% amino acid identity in OST and OSTß shared between humans and little skate, all nine combinations of the and ß peptides from human, mouse, and little skate transported estrone-3-sulfate (7).
Dawson et al. have identified the Ost–Ostß complex as a major contributor to bile acid recirculation by identifying its basolateral location and its transport of taurocholate. The Ost–Ostß transporter is saturable and sodium-independent; it transports a range of substrates similar to those carried by the Oatp transporters found on the basolateral membrane of the hepatocyte, including taurocholate, estrone-3-sulfate, dihydroepiandrosterone sulfate, digoxin, and prostaglandin E2 (7). The contribution of OST–OSTß to bile acid recirculation in humans, the range of its substrate specificity and selectivity, especially regarding drugs, as well as the regulation of the complex’s expression are important topics for future investigations.
Some drugs, such as imipramine, indomethacin, morphine, and pregnenolone may also undergo enterohepatic circulation, in which the parent drugs or their glucuronide conjugates may follow a pathway similar to the one used by bile acids (1). Following systemic blood circulation, drugs undergoing enterohepatic circulation would be taken up into the hepatocyte (by NTCP or OATPs), glucuronidated [by uridine-5'-diphosphate (UDP)-glucuronosyltransferases], then excreted into bile by MRP2 (ABCC2), ABCG2, and/or MDR1 (ABCB1) (Figure 1
). ß-Glucuronidase, present in bacteria inhabiting the gut, hydrolyzes the glucuronide conjugate back to the parent compound, which is then reabsorbed. Although MDR1, MRP2, and ABCG2 are positioned apically on the ileocyte and oriented to prevent further drug absorption (via the basolateral side into the portal blood), upon the entrance of a drug into the ileocyte, basolateral membrane–localized transporters such as OST–OSTß and MRP3 could facilitate drug transport into portal blood (2). The impact of Ost–Ostß and MRP3 on enterohepatic circulation of drugs remains to be established; however, OST–OSTß is probably much more important than MRP3 for recirculation of bile acids. Further studies will elucidate the role of OST–OSTß in enterohepatic circulation and drug absorption, allowing for new strategies in exploiting these pathways for transporter-mediated drug delivery.
|
|
ACKNOWLEDGMENTS
The authors acknowledge the assistance of Ms. Laura Lengowski in the preparation of the figure.
References
–Ostß, is an ileal basolateral bile acid transporter. J. Biol. Chem. Nov. 24 2004 [Epub ahead of print]. Immunolocalization of Ost–Ostß in the mouse ileum, as described in this Viewpoint.
–Ostß were cloned in the little skate.–Ostß. J. Biol. Chem. 278, 27473–27482 (2003).This article has been cited by other articles:
|
|
 |
|
  A.-Q. Sun, N. Balasubramaniyan, K. Xu, C. J. Liu, V. M. Ponamgi, H. Liu, and F. J. Suchy Protein-protein interactions and membrane localization of the human organic solute transporter Am J Physiol Gastrointest Liver Physiol, June 1, 2007; 292(6): G1586 - G1593. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| ASPET Journals | Pharmacological Reviews | Drug Metabolism and Disposition |
| Molecular Interventions | Molecular Pharmacology | J Pharmacology and Exp Therapeutics |
