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 . 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). rOatp1a4 appears to play an important role in cerebrospinal fluid detoxification by limiting the distribution of organic anions to the brain and spinal cord. . In the liver, both transporters are expressed on the basolateral membrane of midzonal to perivenous hepatocytes [3, 4]. While rOatp1a1 binds to the PDZ domain containing 1 (PDZK1) chaperone for its localization to the basolateral plasma membrane of hepatocytes, optimal rOatp1a4 trafficking depends on co-expression and interaction with rOatp1a1; it seems to functionally ‘hitch-hike’ through the cell in this complex . Further, Oatp1a4 was detected on the apical side of the retinal pigment epithelium  as well as in retinal capillary endothelial cells and retinal pigment epithelial cells, thus contributing to the brain-retinal barrier . In the rat ciliary body, Oatp1a4, along with Oatp1a5 and Oatp1b2, was observed mainly on the basolateral surface of the non-pigmented epithelium .
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, 7-9], and it was renamed from Oatp2 upon introduction of the new nomenclature in 2004 . 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 .
On a par with the broad substrate specificity of rOatp1a1, rOatp1a4 transports bile salts, hormones and hormone conjugates like T3, T4 , and dehydroepiandrosterone sulfate; peptides (BQ-123, DPDPE); endogenous opioids like encephalin and leuenkephalin; biotin ; drugs (digoxin, fexofenadine, ouabain, rosuvastatin, pravastatin, doxorubicin); and some organic cations [11-13]. In the blood-brain barrier (BBB), Oatp1a4 transported DPDPE with a higher affinity than rOatp1a1, but did not transport deltorphin II .
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 .
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 . rOatp1a4 expression is also sex-specific in the blood-brain barrier (BBB). Slco1a4 mRNA and Oatp1a4 protein expression levels in the brain microvasculature and the brain uptake of [3H]taurocholate and [3H]atorvastatin were higher in female rats compared to males .
Expression of rOatp1a4 is subject to hormonal regulation. The 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 . Dosing with bone morphogenetic protein 9 (BMP-9) causes the direct activation of the Slco1a4 gene via the transforming growth factor-β (TGF-β)/activin receptor-like kinase 1 (ALK1) signaling pathway .
In rat primary hepatocytes, oxidative stress reduced mRNA levels and decreased transporter function of rOatp1a1 and -1a4, thereby changing the pharmacokinetics of their substrates . 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 .
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 .
Significance in drug disposition
Functionally overlapping with rOatp1a1, rOatp1a4 is responsible for the active hepatocellular uptake of pravastatin and pitavastatin, but not simvastatin [23, 24]. Rosuvastatin uptake of rOatp1a1 was selectively inhibited by digoxin, while 100 μM glyburide inhibited all three rat hepatic Oatps (Oatp1a1, 1a4 and 1b2) . Unlike rOatp1a1, rOatp1a4 was shown to transport digoxin, and is thus a likely player in the hepatobiliary excretion and brain accumulation of this drug [9, 25]. 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 . OATPs, like rOatp1a1, rOatp1a4 and OATP1A2, are partly responsible for fexofenadine disposition, although with differing affinities and capacities . rOatp1a4 transported ouabain with higher affinity than rOatp1a1, suggesting that rOatp1a4 may play the dominant role in ouabain transport in the rat liver . 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 . 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 . 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 .
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