The organic anion transporting polypeptide (OATP) family of drug transporters are divided into 6 families as determined by their amino acid composition. In total 11 OATPs have been discovered and they are encoded by the SLCO genes. OATPs transport a large number of structurally diverse substrates including bile salts and steroid hormones (Roth et al, 2012).
1.4.3.1 Tissue expression
There is ubiquitous expression of OATP1A2 mRNA in the brain, liver, lung and kidney. OATP1A2 protein is highly expressed in liver cholangiocytes (Lee et al, 2005), the apical membrane of the distal nephrons (Lee et al, 2005) and the luminal surface of blood brain barrier (Bronger et al, 2005). This particular protein expression is highly suggestive of OATP1A2 having a significant role in excretion of xenobiotic drugs into the bile and also excretion of drugs into the urine and maintenance of the blood brain barrier. OATP1B1 and OATP1B3 are also expressed in the liver, but their pattern of distribution varies, with OATP1B1 expressed throughout the lobule while OATP1B3 is mainly located around the central vein (Konig et al, 2000). OATP1C1 protein expression is found in the testes (Pizzagalli et al, 2002) and the choroid plexus (Roberts et al, 2008). OATP2A1 is a
prostaglandin transporter with protein expression present in the body and antrum of the stomach (Mandery et al, 2010). OATP2B1 protein is predominately expressed in skeletal muscle (Knauer et al, 2010) and basolateral surface of the syncytiotrophoblasts (St-Pierre et al, 2002), nephrons and hepatocytes (Roth et al, 2012). mRNA expression of OATP3A1 is found in the testis, heart and brain (Adachi et al, 2003). OATP4A1 and OATP4C1 protein expression is found in placenta (Sato et al, 2003) and kidney (Mikkaichi et al, 2004) respectively. OATP5A1 mRNA expression is present in the prostate, skeletal muscle and thymus, while OATP6A1 mRNA is found in the testes (Suzuki et al, 2003).
1.4.3.2 Substrate specificity
The method of OATP transport of substrates is still unclear. It is accepted that OATP transport is ATP and sodium independent. Individual members of the OATP family may use different exchangers such as bicarbonate (Satlin et al, 1997), glutathione (Li et al, 1998) and glutathione conjugates (Li et al, 2000) to facilitate movement of their substrates. Glutathione exchange is not required for OATP1B1 and OATP1B3 transport (Mahagita et al, 2007). The net exchange is always electro neutral. It has been proposed that substrates translocate down a positively charged pore by a rocker switch process (Meier-Abt et al, 2005). OATPs are able to function as bidirectional transporters and transport efficiency is affected by pH (Roth et al, 2012). Acidic conditions are associated with increased OATP2B1 transport activity (Varma et al, 2011) by potentially protonating the histidine residue on the extracellular trans membrane domain 3 (Mahagita et al, 2007). This may influence intestinal absorption as this transporter is expressed in the stomach.
Substrates transported by the OATP family are generally anions with amphipathic properties and a molecular weight greater than 350mg. However, some OATPs are capable of transporting cationic drugs (Bossuyt et al., 1996). The known endogenous substrates transported by the OATP family are bile salts, steroids and thyroid hormones. Estrone-3-sulphate (E-3-S) is a substrate which is transported by most OATP transporters and along with bromosulphophthalein is considered a model substrate. Substrates share in common a hydrogen bond donor, two hydrophobic regions and two hydrogen bond acceptors (Chang et al, 2005). Substrates can bind to numerous sites on the OATP protein which correspond to either high or low affinity binding site interactions and hence differential transport kinetics. E-3-S has biphasic kinetics when transported by OATP1B1 supporting this concept of varying strengths of substrate binding potential to a transporter (Noe et al, 2007).
1.4.3.3 Regulation of expression
OATP expression is predominately governed by a diverse family of transcriptional factors belonging to the Hepatocyte nuclear factor (HNF) family. OATP1B1 expression in hepatocytes is determined by a combination of factors including HNF1α (Furihata T et al, 2007), STAT5 (Wood et al, 2005) and IL-1 (Le Vee et al, 2008). OATP1B3 expression is decreased by increasing levels of HNF3β, possibly by the transcription factor binding to the promoter site for the OATP1B3 and impairing RNA polymerase activity (Vavricka SR et al, 2004). OATP1A2 expression in the liver is influenced by an increase in bile acid concentrations, affecting expression in the liver and small bowel (Kullak-Ublick et al, 1997).
OATP protein expression is also regulated by PDZ proteins. PDZ proteins have a role in attaching transmembrane proteins, such as OATP, to the cytoskeleton (Ranganathan et al, 1997). The majority of OATP proteins have PDZ consensus sequences (Wang et al, 2005) which can interact with PDZ proteins and affect OATP protein stability at the membrane surface (Kato et al, 2004).
1.4.3.4 Transporter structure
The general size of the OATP proteins varies between 643-724 amino acids in length. They have 12 transmembrane domains (Wang et al, 2008) and both the amine and carboxyl group termini are located intracellularly. N-glycoslyation sites are relatively conserved at the 2nd and 5th extracellular domains, but the sites vary between proteins. The crystal structure for the OATP proteins has yet to be determined hence the amino acid interactions important for substrate translocation
are yet to be confirmed. However, chimera studies have shown extracellular domains 8,9 and 10 are important for substrate transfer in OATP1B1 (Gui et al, 2009) while extracellular domain 10 is important for substrate passage in OATP1B3 (Giu et al, 2008). Crystallography and nuclear magnetic resonance studies will help determine the exact amino acids involved in substrate binding and translocation.
1.4.3.5 Pathology and significance
Certain clinical conditions have been associated with an altered expression of OATP mRNA and protein expression. Inflammatory bowel disease is known to be associated with increased OATP2B1 and OATP4A1 mRNA expression levels (Wojtal et al, 2009). Cholestasis due to any aetiology can lead to a reduction in mRNA levels of OATP1A2, OATP1B1 and OATP1B3 in the liver (Kietal et al, 2005; Chen et al, 2008; Congiu et al, 2009).
The expression of OATPs also changes with different types of cancer. Gastric, pancreatic and colonic cancers have been associated with OATP1B3, which is normally localised to the liver only (Abe et al, 2001; Lee et al, 2008). However, in hepatocellular carcinoma, the expression of OATP1B3 is decreased (Vavricka et al, 2004). The high expression of OATP in some cancers may provide a survival advantage, as some cancers are known to proliferate in response to certain hormones, and hormones are the natural substrates for the OATP family.