ReviewThe SLCO (former SLC21) superfamily of transporters☆
Introduction
Cells continuously need to take up nutrients as well as signaling molecules and to release metabolic endproducts for disposal. Most such substances, even if very lipopophilic, are not able to diffuse across plasma membranes and consequently need transport proteins to cross the cell boundaries. This is exemplified by cholesterol, which takes advantage of (transport) proteins to cross plasma membranes. For example, cholesterol absorption in the small intestine is mediated, at least in part, by the Niemann-Pick 1-like 1 (NPC1L1) protein (Lecerf and de Lorgeril, 2011), which is susceptible to inhibition by the drug ezetimibe. Else, release of cholesterol from the canalicular membrane of hepatocytes into bile is facilitated by the heterodimeric ATP-binding-cassette (ABC) transporter ABCG5/ABCG8 (Hazard and Patel, 2007). Bilirubin, the metabolic endproduct of the breakdown of heme, is practically water insoluble and has for a long time been assumed to enter hepatocytes by simple diffusion. While the issue of transmembrane movement of bilirubin was controversially discussed (diffusion across lipid bilayer versus involvement of protein(s) (Ostrow et al., 1994)), several groups have now provided solid evidence for the involvement of organic anion transporting polypeptides (OATPs) in bilirubin uptake into hepatocytes (see below). From these prototypic results, it is safe to extrapolate that most substances and even highly non-polar or lipophilic compounds require transmembrane transport proteins to be moved between the extracellular space and the cytoplasm. The importance of transport proteins in the disposition of drugs is also gaining wide acceptance (Dobson et al., 2009, Fenner et al., 2012). The solute carrier superfamily (SLC) covers hundreds of proteins mediating the plasma membrane crossing of small molecules or solutes of various degrees of hydrophilicity and lipophilicity (Hediger et al., 2004). Among the SLC superfamily members, OATPs play a prominent role in transporting endo- as well as xeno-biotics including numerous drugs across plasma membranes.
In recent years, considerable progress has been made in identifying endogenous substrates of OATPs, in elucidating the roles OATPs play in drug disposition and transport of toxins, as well as in the characterization of genetic variants. In this overview on the current status of OATP research, we do not attempt to summarize the so far characterized drugs and xenobiotics, which have been identified as OATP substrates as this information can be found in several recent reviews (Fahrmayr et al., 2010, Giacomini et al., 2010, Hagenbuch and Gui, 2008, Kalliokoski and Niemi, 2009, Konig, 2011, Kusuhara and Sugiyama, 2009, Roth et al., 2012).
Section snippets
Phylogenesis of OATPs
The first OATP, rat OATP1A1 (originally called Oatp) was isolated in 1994 using expression cloning (Jacquemin et al., 1994) and the first human OATP, OATP1A2 (originally called OATP) was isolated a year later by hybridization screening (Kullak-Ublick et al., 1995). In the following years several additional OATPs from humans and rodents were identified and characterized and we know today that there are eleven OATPs in humans. In 2004, an amino acid sequence based classification and nomenclature
Endogenous substrates of OATPs
Rat OATP1A1, the founding member of the SLCO superfamily of organic anion transporters, was isolated with an expression-cloning approach using the anion bromosulphophthalein as substrate (Hagenbuch and Meier, 2004, Jacquemin et al., 1994). Functional characterization of rat OATP1A1 in heterologous expression systems revealed that it can transport bile acids (e.g. cholate) and bile acid conjugates (e.g. taurocholate) (Eckhardt et al., 1999, Jacquemin et al., 1994) in a sodium-independent way
Tissue distribution
The expression of OATPs has been studied both at the mRNA and the protein level. In general, OATPs have been detected in essentially every organ in epithelial or endothelial cells. Some OATPs have a restricted expression and are therefore assumed to be organ specific, while others are expressed ubiquitously. Examples for such a restricted expression are the two human transporters OATP1B1 and OATP1B3 that are considered to be liver-specific (Roth et al., 2012) or the brain-specific OATP1C1
Transport mechanisms of OATPs
The mechanism(s) by which OATPs transport is(are) not fully understood, but OATPs are believed to act as organic anion exchangers (Hagenbuch and Gui, 2008). In 1997 bicarbonate was identified as the first counterion in experiments with rat OATP1A1 expressed in HeLa cells (Satlin et al., 1997). Additional experiments demonstrated that reduced glutathione and glutathione conjugates could act as counter ions. Transport of taurocholate and leukotriene C4 mediated by rat OATP1A1 was trans-stimulated
Regulation of expression and modulation of function
Regulation of OATP expression has been documented at the transcriptional as well as at the post-translational level. Early studies demonstrated that expression of the liver specific OATP1B1 and OATP1B3 was controlled by the liver enriched hepatocyte nuclear factor 1α (HNF1α) (Jung et al., 2001). In hepatocellular carcinoma (HCC), expression of OATP1B3 was shown to be decreased while expression of OATP1B1 was normal at the mRNA level or slightly decreased at the protein level (Cui et al., 2003,
Structure–function relationship
Based on hydrophobicity analyses, experimental data available from rat OATP1A1 (Jacquemin et al., 1994, Wang et al., 2008) and homology modeling, OATPs are 12 transmembrane domain proteins with the amino- and the C-terminal ends located at the cytoplasmic side of the membrane (Fig. 3A). Because so far no crystal structure data are available, homology modeling was used to predict a putative three-dimensional model (Fig. 3B). Furthermore, several groups have used chimeric approaches combined with
Mutations and polymorphisms of OATPs
So far, few pathophysiologic conditions related to mutations in SLCO genes have been reported. Mesolemia-synosteses syndrome (OMIM600383) is a rare disease and includes mesomelic limb shortening and acral synosthoses (Isidor et al., 2009). This syndrome has been linked to a disturbance in sulfate metabolism and/or homoestasis (Dawson, 2011). Cytogenetic analysis of 5 patients from four families with this disease identified a submicroscopic microdeletion on chromosome 8q13 (Isidor et al., 2010).
Conclusion and outlook
Since the cloning of the first OATP, the SLCO family members have made it to center stage in drug development (Giacomini et al., 2010) and in the understanding of drug disposition (Fenner et al., 2012). While the progress in developing tools for understanding the role of OATPs in handling of endo- and xenobiotics has been enormous, knowledge on their molecular transport mechanisms and on their structure is clearly lagging behind. Both areas are however highly relevant for developing better
Acknowledgements
The authors would like to acknowledge the National Institutes of Health Grants RR021940 and GM077336, the Swiss National Science Foundation Grant # 31003A_124652 for their support, and thank Melanie Hagenbuch for her help with the artwork.
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