Oatp1a4 - rat

Oatp1a4 (organic anion transporting protein 1a4), rat

Aliases: AI785519, Oatp2, Slc21a5
Gene name: Solute carrier organic anion transporter, family member 1a4 (Slco1a4)

Rat Oatp1a4 is a sodium-independent, broad substrate range bile salt and organic anion transporter expressed in the brain, liver, retina and ciliary body. rOatp1a4 largely overlaps with rOatp1a1 with respect to both substrate profile and localization, and it is thought to contribute significantly to the liver uptake of bile salts, hormone conjugates and peptides, the hepatic disposition of anionic drugs, as well as drug transport through the blood-brain and blood-retinal barriers. Expression levels of rOatp1a4 are sex- and age-dependent, and respond to hormones, drug induction, and oxidative stress.
In the rat brain, strong rOatp1a4 signals were observed in the hippocampal pyramidal and dentate granule cells, in cerebellar Purkinje and granule cell layers, while moderate signal was observed in the choroid plexus [1]. rOatp1a4 is localized on both the abluminal and luminal membrane domains of brain capillary endothelial cells. On choroid plexus epithelial cells, rOatp1a4 localizes at the basolateral side, while rOatp1a1 is expressed on the apical surface, which indicates complementary functions of rOatp1a1 and -1a4 in relation to the cerebrospinal fluid (Gao et al., 1999). In the liver, both transporters are expressed on the basolateral membrane of midzonal to perivenous hepatocytes [2, 3]. Further, Oatp1a4 was detected on the apical side of the retinal pigment epithelium [4] as well as in retinal capillary endothelial cells and retinal pigment epithelial cells, thus contributing to the brain-retinal barrier [5]. In the rat ciliary body, Oatp1a4, along with Oatp1a5 and Oatp1b2, was observed mainly on the basolateral surface of the non-pigmented epithelium [6].
rOatp1a4 was identified in 1997 in the rat brain and liver, and later also found in the retina and the ciliary body. rOatp1a4 shares 77% amino acid sequence identity with the earlier identified rOatp1a1 [1, 5-7], and it was renamed from Oatp2 upon introduction of the new nomenclature in 2004 [8]. Oatp1a4, similar to other OATPs/Oatps, has 12 transmembrane domains (TM) with a large extracellular loop between TM9 and 10, contains conserved cysteine residues, N-glycosylation sites, and conserved amino acids [9].
On a par with the broad substrate specificity of rOatp1a1, rOatp1a4 transports bile salts, hormones and hormone conjugates, peptides (BQ-123, DPDPE), drugs (biotin, digoxin, fexofenadine, ouabain, pravastatine) and some organic cations [9]. rOatp1a4 was able to transport taurocholate, cholate, 17b-estradiol-glucuronide, estrone-3-sulfate and ouabain, the latter with higher affinity than rOatp1a1, suggesting that rOatp1a4 may play the dominant role in ouabain transport in the rat liver. Unlike rOatp1a1, rOatp1a4 was shown to transport digoxin, and is thus a likely player in the hepatobiliary excretion and brain accumulation of this drug [7]. Organic anion transporters can also mediate hepatocellular uptake of type II organic cations. The strongest uptake of N-(4, 4-azo-n-pentyl)-21-deoxy-ajmalinium was observed in the case of OATP1A2, followed by rOatp1a4 and rOatp1a1 [10]. OATPs, like rOatp1a1, rOatp1a4 and OATP1A2, are partly responsible for fexofenadine disposition, although with differing affinities and capacities [11]. rOatp1a4 was able to transport hormones like T3, T4 [1], and dehydroepiandrosterone sulfate; endogenous opioids like encephalin and leuenkephalin; as well as biotin [3]. In the blood-brain barrier (BBB), Oatp1a4 transported DPDPE with a higher affinity than rOatp1a1, but did not transport deltorphin II [12]. Functionally overlapping with rOatp1a1, rOatp1a4 was responsible for the active hepatocellular uptake of pravastatin and pitavastatin, but not simvastatin [13, 14]. Nafcillin, a model beta-lactam antibiotic showing extensive biliary excretion, was taken up by isolated rat hepatocytes, and this transport could be inhibited with estrone-3-sulfate and sulfobromophthalein. rOatp1a1, -1a4, and -1b2 all transported nafcillin, but rOatp1a4 was the predominant contributor to its hepatic uptake [15](Nakakariya et al., 2007). Hepatic clearance of eprosartan, an angiotensin II receptor antagonist, was mediated by OATP1B1 as well as rOatp1a1 and rOatp1a4 on the uptake side, and MRP2/rMrp2 on the efflux side [16]. The alkaloid berberine is accumulated in hepatocytes, and OATP1B3/rOatp1a1/rOatp1a4 are thought to be responsible for its liver disposition. rOatp1a4 expression in hepatocytes was up-regulated by a 24-h berberine treatment, whereas the expression levels of the P-gp and Bcrp were significantly downregulated [17].
During rat brain maturation from the early postnatal stage to the adult, rOatp1a4 expression increases progressively; however, its transport activity declines. It has been shown that nuclear β-catenin expression decreases with brain maturation, and it is inversely correlated with expression changes of Bcrp, P-gp, Oat3, and Oatp1a4 transporters. Thus, high expression of these transporters is associated with the downregulation of β- catenin [18].
rOatp1a4 expression in the liver, like that of rOatp1a1, is age- and sex-dependent. rOatp1a4 is low in the fetal liver, and increases postnatally with age. Liver expression of rOatp1a4 is lower in females than in males, while in mice this relation is opposite [19].
Expression of rOatp1a4 is also subject to hormonal regulation. Aryl hydrocarbon receptor downregulates hepatic rOatp1a4 mRNA. Constitutive androstane receptor reduces levels of Oatp1a1 but increases expression of Oatp1a4 in the rat and mouse liver. Pregnane X receptor ligands like pregnenolone-16-carbonitrile increase mRNA expression of rOatp1a4 [20].
In rat primary hepatocytes, oxidative stress reduced mRNA levels and decreased transporter function of rOatp1a1 and -1a4, thereby changing the pharmacokinetics of their substrates [21]. In brain diseases such as brain injury, cerebral edema, mountain sickness, apnoe, and stroke, hypoxia/reoxygenation stress in the brain may modulate transporters in the BBB. rOatp1a4 functional expression was increased during hypoxia and subsequent reoxygenation, with the presumable involvement of TGF-b/ALK5 signaling [22].
The expression of hepatic uptake and efflux transporters is altered in cholestasis. Alpha-naphthylisothiocyanate (ANIT) is a toxicant used to induce intrahepatic cholestasis in rodents. In ANIT-treated rats, expression of rOatp1a1 and -1b2, but not of rOatp1a4, was decreased. Co-treatment with dioscin, a saponin that protects against hepatotoxicity, was able to counter downregulation of rOatp1a1 and -1b2, and increase protein levels of rOatp1a4. Dioscin alone upregulated all three transporters [23].

 

References

1.    Abe, T., et al., Molecular characterization and tissue distribution of a new organic anion transporter subtype (oatp3) that transports thyroid hormones and taurocholate and comparison with oatp2. J Biol Chem, 1998. 273(35): p. 22395-401.
2.    Reichel, C., et al., Localization and function of the organic anion-transporting polypeptide Oatp2 in rat liver. Gastroenterology, 1999. 117(3): p. 688-95.
3.    Kakyo, M., et al., Immunohistochemical distribution and functional characterization of an organic anion transporting polypeptide 2 (oatp2). FEBS Lett, 1999. 445(2-3): p. 343-6.
4.    Gao, B., et al., Localization of organic anion transport protein 2 in the apical region of rat retinal pigment epithelium. Invest Ophthalmol Vis Sci, 2002. 43(2): p. 510-4.
5.    Akanuma, S., et al., Localization of organic anion transporting polypeptide (Oatp) 1a4 and Oatp1c1 at the rat blood-retinal barrier. Fluids Barriers CNS, 2013. 10(1): p. 29.
6.    Gao, B., et al., Localization of organic anion transporting polypeptides in the rat and human ciliary body epithelium. Exp Eye Res, 2005. 80(1): p. 61-72.
7.    Noe, B., et al., Isolation of a multispecific organic anion and cardiac glycoside transporter from rat brain. Proc Natl Acad Sci U S A, 1997. 94(19): p. 10346-50.
8.    Hagenbuch, B. and P.J. Meier, Organic anion transporting polypeptides of the OATP/ SLC21 family: phylogenetic classification as OATP/ SLCO superfamily, new nomenclature and molecular/functional properties. Pflugers Arch, 2004. 447(5): p. 653-65.
9.    Hagenbuch, B. and P.J. Meier, The superfamily of organic anion transporting polypeptides. Biochim Biophys Acta, 2003. 1609(1): p. 1-18.
10.    van Montfoort, J.E., et al., Polyspecific organic anion transporting polypeptides mediate hepatic uptake of amphipathic type II organic cations. J Pharmacol Exp Ther, 1999. 291(1): p. 147-52.
11.    Cvetkovic, M., et al., OATP and P-glycoprotein transporters mediate the cellular uptake and excretion of fexofenadine. Drug Metab Dispos, 1999. 27(8): p. 866-71.
12.    Gao, B., et al., Organic anion-transporting polypeptides mediate transport of opioid peptides across blood-brain barrier. J Pharmacol Exp Ther, 2000. 294(1): p. 73-9.
13.    Tokui, T., et al., Pravastatin, an HMG-CoA reductase inhibitor, is transported by rat organic anion transporting polypeptide, oatp2. Pharm Res, 1999. 16(6): p. 904-8.
14.    Kikuchi, R., et al., Involvement of multiple transporters in the efflux of 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors across the blood-brain barrier. J Pharmacol Exp Ther, 2004. 311(3): p. 1147-53.
15.    Nakakariya, M., et al., Predominant contribution of rat organic anion transporting polypeptide-2 (Oatp2) to hepatic uptake of beta-lactam antibiotics. Pharm Res, 2008. 25(3): p. 578-85.
16.    Sun, P., et al., OATP and MRP2-mediated hepatic uptake and biliary excretion of eprosartan in rat and human. Pharmacol Rep, 2014. 66(2): p. 311-9.
17.    Chen, C., et al., Organic anion-transporting polypeptides contribute to the hepatic uptake of berberine. Xenobiotica, 2015. 45(12): p. 1138-46.
18.    Harati, R., et al., P-glycoprotein, breast cancer resistance protein, Organic Anion Transporter 3, and Transporting Peptide 1a4 during blood-brain barrier maturation: involvement of Wnt/beta-catenin and endothelin-1 signaling. Mol Pharm, 2013. 10(5): p. 1566-80.
19.    Hou, W.Y., et al., Age- and sex-related differences of organic anion-transporting polypeptide gene expression in livers of rats. Toxicol Appl Pharmacol, 2014. 280(2): p. 370-7.
20.    Klaassen, C.D. and L.M. Aleksunes, Xenobiotic, bile acid, and cholesterol transporters: function and regulation. Pharmacol Rev, 2010. 62(1): p. 1-96.
21.    Tsujimoto, T., et al., Effect of oxidative stress on expression and function of human and rat organic anion transporting polypeptides in the liver. Int J Pharm, 2013.
22.    Thompson, B.J., et al., Hypoxia/reoxygenation stress signals an increase in organic anion transporting polypeptide 1a4 (Oatp1a4) at the blood-brain barrier: relevance to CNS drug delivery. J Cereb Blood Flow Metab, 2014. 34(4): p. 699-707.
23.    Zhang, A., et al., Dioscin protects against ANIT-induced cholestasis via regulating Oatps, Mrp2 and Bsep expression in rats. Toxicol Appl Pharmacol, 2016. 305: p. 127-35.

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