Pharmacogenomics of organic anion-transporting polypeptides (OATP)
Introduction
The members of the organic anion-transporting polypeptides (OATP) represent a family of important proteins (SLC21A) involved in the membrane transport of endogenous and xenobiotic compounds. Rat Oatp1 (Oatp1), the first member of this family, was identified by expression cloning and was shown to have properties of a sodium-independent organic anion transporter [1]. Since that time, at least six OATPs have been identified and characterized in rodents (rats or mice) while eight OATPs are known in humans. Recent identification of OATPs in the little skate, demonstrate that these proteins are evolutionarily ancient [2]. It is worth noting, however, that difficulty exists in classifying OATPs from rodents and humans as orthologous since amino acid sequence homologies are often low. Furthermore, the various nomenclatures for OATPs among different species often suggest orthology when such is not the case and this situation has lead to some confusion [3]. For example, rat Oatp2 is not orthologous to human OATP2, a transporter which is also known as liver-specific transporter 1 (LST-1) or OATP-C. Therefore, a convention has been established that the human OATPs be named alphabetically in capital letters (i.e., OATP-A, OATP-B, etc.; Table 1) and numerically for rodent forms (i.e., Oatp1, Oatp2, etc.) with capital ‘O’ for rat and small ‘o’ for mouse [4], [5].
OATPs are expressed in a wide variety of tissues including the liver, kidney, brain, and small intestine (Table 1). In liver, all known OATPs are localized to the basolateral membrane and participate in the vectorial transport of solutes from blood to bile [6], [7] (Fig. 1). In renal proximal tubules, Oatp1 is expressed on the brush border (apical) membrane [8], suggesting that this transporter facilitates solute reabsorption from urine. Rat Oatp3 has been localized to the apical membrane of the enterocyte and it is thought to be involved in organic solute absorption from the gastrointestinal tract [9]. Solute permeability across the blood–brain barrier is enhanced by the expression of Oatp2 in brain capillary endothelial cells where interestingly, this transporter is localized at both the apical and basolateral poles [10]. At the choroids plexus, Oatp1 and Oatp2, localized on the apical and basolateral membranes, respectively, act in concert to facilitate the removal of organic solutes from the cerebrospinal fluid [10], [11]. Rat Oatp2 is localized on the apical membrane of retinal pigment epithelia and appears to be responsible for retinoid transport [12]. Thus, OATPs are found in a variety of epithelial and endothelial cells in different tissues facilitating the transcellular flux of solutes.
Endogenous compounds, such as thyroid hormones, bilirubin, prostaglandins, bile acids, steroids and cholecystokinin, are substrates of the OATPs (Table 1), indicating that these transporters participate in a variety of important physiological processes. This is clearly exemplified in the observations which show hepatic expression of OATPs is altered as a protective response to cholestasis [13], [14], [15] and in primary biliary cholangitis [16]. It also is being recognized that OATPs are capable of transporting structurally diverse drugs and xenobiotics such as organic anions, cations and neutral or zwitterionic compounds as well as certain peptidomimetic agents (Table 1). Thus, the title of organic anion-transporting polypeptide is somewhat of a misnomer. With the ever-increasing numbers of drug substrates and inhibitors being identified for OATPs, an important role for these transporters in drug disposition is becoming apparent. This is highlighted by the observation that inhibition of OATPs by fruit juices can markedly decrease the bioavailability of the antihistaminic drug, fexofenadine [17].
The mechanism(s) by which the OATPs transport solutes has not been clearly elucidated. Studies involving rat Oatps suggest possible bicarbonate or glutathione exchange mechanisms [18], [19], [20], although this remains a topic of debate [21]. Furthermore, regulation of OATP function and expression has become a rapidly evolving area of research. For example, recent studies have demonstrated that OATP transport function is decreased in response to protein phosphorylation [22], [23]. In addition, it now is evident that OATP expression can be induced by various xenobiotics that are known ligand activators of the adopted nuclear receptors pregnane X receptor (PXR) and constitutive androstane receptor (CAR) [23], [24], [25], [26]. Finally, the constitutive expression of several liver-specific OATPs including OATP-C, OATP8 and Oatp4 have been shown to be under direct transcriptional control by hepatocyte nuclear factor 1α [27].
With the recognition that OATPs possess broad substrate specificity, it seems likely that functionally deleterious genetic variations in the human OATPs may provide a basis for interindividual differences in drug disposition and response. In the following section, specific details on the distribution and substrate specificities of human OATPs are provided including available information regarding the identities and functional relevance of known genetic variations. A list of genetic polymorphisms in human OATPs is provided (Table 2) based on the published accounts, comparisons of deposited cDNA sequences and data from a public database (dbSNP, www.ncbi.nlm.nih.gov/SNP/).
Section snippets
OATP-A
The first human OATP, OATP-A (previously named OATP), was isolated from human liver [28]. Despite the fact that OATP-A has been reported to be expressed in various tissues such as liver, brain, lung, kidney and testes by Northern blot analysis [28] and in liver by immunochemical analysis [29], a restricted brain distribution has been suggested by others [30]. Indeed OATP-A mRNA is widespread in the brain [31] and immunodetectable protein can be found in brain capillary endothelial cells [32],
Conclusions
Since the discovery of the first OATP by Jacquemin et al. [1], there has been much progress in the identification and characterization of the various members of this transporter family in different species. For the human OATPs, the liver expressed transporters (OATP-B, -C and 8) have been studied most extensively and their important role in the hepatocellular uptake of solutes, well established. Similarly, OATP-A is likely an important determinant in the blood–brain barrier permeability of
Acknowledgments
Work done in our laboratory is supported by US Public Health Service Grants GM54724 and GM31304.
References (56)
- et al.
Molecular identification and characterization of novel members of the human organic anion transporter (OATP) family
Biochem. Biophys. Res. Commun.
(2000) - et al.
Organic anion-transporting polypeptide B (OATP-B) and its functional comparison with three other OATPs of human liver
Gastroenterology
(2001) - et al.
Effects of ursodeoxycholic and cholic acid feeding on hepatocellular transporter expression in mouse liver
Gastroenterology
(2001) - et al.
Hepatobiliary transporter expression in percutaneous liver biopsies of patients with cholestatic liver diseases
Hepatology
(2001) - et al.
Organic anion transporting polypeptide mediates organic anion/HCO3-exchange
J. Biol. Chem.
(1997) - et al.
Identification of glutathione as a driving force and leukotriene C4 as a substrate for oatp1, the hepatic sinusoidal organic solute transporter
J. Biol. Chem.
(1998) - et al.
Down-regulation by extracellular ATP of rat hepatocyte organic anion transport is mediated by serine phosphorylation of Oatp1
J. Biol. Chem.
(2000) - et al.
Differential effects of microsomal enzyme-inducing chemicals on the hepatic expression of rat organic anion transporters, OATP1 and OATP2
Hepatology
(2001) - et al.
Characterization of the human OATP-C (SLC21A6) gene promoter and regulation of liver-specific OATP genes by hepatocyte nuclear factor 1α
J. Biol. Chem.
(2001) - et al.
Molecular and functional characterization of an organic anion transporting polypeptide cloned from human liver
Gastroenterology
(1995)
Chlorambucil-taurocholate is transported by bile acid carriers expressed in human hepatocellular carcinomas
Gastroenterology
Identification of a novel gene family encoding human liver-specific organic anion transporter LST-1
J. Biol. Chem.
Dehydroepiandrosterone sulfate (DHEAS): identification of a carrier protein in human liver and brain
FEBS Lett.
Bile acid transport and regulating functions in the human biliary epithelium
Hepatology
Multispecific amphipathic substrate transport by an organic anion transporter of human liver
J. Hepatol.
Identification and functional characterization of the promoter region of the human organic anion transporting polypeptide gene
Hepatology
A novel human hepatic organic anion transporting polypeptide (OATP2). Identification of a liver-specific human organic anion transporting polypeptide and identification of rat and human hydroxymethylglutaryl-CoA reductase inhibitor transporters
J. Biol. Chem.
LST-2, a human liver-specific organic anion transporter, determines methotrexate sensitivity in gastrointestinal cancers
Gastroenterology
Polymorphisms in OATP-C: Identification of multiple allelic variants associated with altered transport activity among European- and African-Americans
J. Biol. Chem.
Hepatic uptake of bilirubin and its conjugates by the human organic anion transporter SLC21A6
J. Biol. Chem.
Localization and genomic organization of a new hepatocellular organic anion transporting polypeptide
J. Biol. Chem.
Hepatic uptake of cholecystokinin octapeptide by organic anion-transporting polypeptides OATP4 and OATP8 of rat and human liver
Gastroenterology
Expression cloning of a rat liver Na(+)-independent organic anion transporter
Proc. Natl. Acad. Sci. USA
An evolutionarily ancient Oatp: insights into conserved functional domains of these proteins
Am. J. Physiol.
Organic anion transporting polypeptides, cholestasis, and nuclear receptors (letter)
Hepatology
Vectorial transport by double-transfected cells expressing the human uptake transporter SLC21A8 and the apical export pump ABCC2
Mol. Pharmacol.
Transcellular transport of organic anions across a double-transfected Madin-Darby canine kidney II cell monolayer expressing both human organic anion-transporting polypeptide (OATP2/SLC21A6) and multidrug resistance-associated protein 2 (MRP2/ABCC2)
J. Biol. Chem.
Immunologic distribution of an organic anion transport protein in rat liver and kidney
Am. J. Physiol.
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