Aliases: OATP, OATP-A, SLC21A3
Gene name: Solute carrier organic anion transporter family member 1A2 (SLCO1A2)
OATP1A2, the first identified human OATP, is an uptake transporter with widespread tissue expression. It has broad substrate specificity, including endogenous amphipathic substrates as well as pharmacological drugs and xenobiotics. It is expressed in all major organs, particularly on the apical surface of enterocytes and cholangiocytes (in contrast to OATP1B1 and 1B3, which are both expressed on the basolateral surface of hepatocytes), as well as in the brain, lung, kidney, and testis [1-3]. Its expression in the liver and gastrointestinal tract (GIT) is altered in the presence of excess bile acids (although the data are somewhat ambiguous), and expression can also be influenced by steroid receptors and the vitamin D receptor. The clinical relevance of this remains unclear. Given the promiscuity of this transporter, and its expression in organs of relevance to drug disposition and response, genetic variations in SLCO1A2 have the potential for significant pharmacologic and toxicological consequences. Once again, the clinical relevance of these observations remains to be clearly demonstrated. However, OATP1A2 is notably inhibited in the human GIT by components of fruit juice, which decrease the oral bioavailability of the OATP1A2 (and MDR1) substrate fexofenadine [4-6]. Although the evidence indicates that OATP1A2-mediated oral absorption of some drugs is modified by foods, and that this transporter has broad substrate specificity for important therapeutic drug classes, neither the FDA nor the EMA guidance specifically recommend the study of OATP1A2 interactions for NCEs.
OATP1A2 mRNA is expressed in all major organs of the human body [1-3, 7]. In the intestine, OATP1A2 protein is localized to the brush border (apical) membrane of enterocytes in the duodenum, where it is implicated in the oral absorption of xenobiotics . Within the liver, OATP1A2 is exclusively expressed on the apical (biliary) membrane of cholangiocytes, and may be involved in the reabsorption of substrates that have been excreted into the bile . In the kidney, OATP1A2 is expressed at the apical (urine) membrane of the distal nephron, where it may be responsible for either reabsorption or secretion of xenobiotics into urine . OATP1A2 is also expressed apically in capillary endothelial cells of the blood–brain barrier (BBB)  and in retinal pigment epithelial cells , and it is found in the red blood cell membrane .
OATP1A2 expression in normal nonmalignant breast tissue is low as compared with other members of the OATP family. However, expression in lactating mammary epithelium cells (MEC) is significantly greater than non-lactating MECs, suggesting a regulated physiological function of this transporter in breast tissue [12, 13].
Function, physiology, and clinically significant polymorphisms
OATP1A2 is an integral membrane protein, predicted to contain 12 membrane-spanning domains. It is generally regarded as a unidirectional uptake transporter. In common with many other OATPs, the driving forces facilitating its transport activity remain somewhat unclear. OATP1A2 transports a diverse range of organic anionic, neutral, cationic and amphipathic xenobiotic and endogenous molecules, including bile acids, conjugated sex steroids, T3 and T4, linear and cyclic peptides, mycotoxins, prostaglandin E2, fexofenadine, ouabain, and statins [2, 7, 14-16]. Several drugs, such as saquinavir, lovastatin, verapamil, dexamethasone and naloxone, and food components such as fruit juices and naringin, inhibit OATP1A2-mediated substrate uptake in vitro . The exact properties of OATP1A2-mediated transport are pH-dependent: different transport kinetics were observed under lower pH conditions, such as those found in the microenvironments of the small intestinal mucosa and renal distal tubules, compared to neutral pH conditions .
High expression of OATP1A2 in the BBB, kidney, and liver, and its affinity for T3 and T4, indicate a potentially important role in the delivery of thyroid hormones to the kidney and across the BBB, as well as elimination by the liver . OATP1A2 is essential to all-trans-retinol uptake by retinal pigment epithelial cells, which is part of the canonical visual cycle .
Cholestasis has been associated with decreased mRNA levels of hepatic OATP1A2, OATP1B1, and OATP1B3 [20, 21]. However, other studies report up-regulation of OATP1A2 expression in the small intestine and liver in response to increased bile acid levels . Similarly, placental expression of OATP1A2 mRNA is increased in patients with intrahepatic cholestasis during pregnancy . Albeit contradictory, these studies indicate a direct or indirect role for OATP1A2 in bile salt transport.
The expression of OATPs is largely controlled by transcriptional regulation, and OATP1A2 is no exception. In breast carcinoma tissues and cell lines, OATP1A2 expression is significantly associated with the expression of the steroid and xenobiotic receptor (SXR) . Regulation of OATPs can also occur at the protein level. As most OATPs contain a PDZ consensus sequence , and the carboxyl terminus of OATP1A2 has been shown to interact with PDZ proteins, membrane localization of OATPs may be due to interactions with PDZ proteins . Protein kinase C (PKC) regulates the transport function of OATP1A2 by modulating protein internalization; this effect of PKC is mediated in part by clathrin-dependent pathways in an in vitro cell model . Targeting, internalization, and recycling of OATP1A2 is also dependent on casein kinase 2 .
A role for PXR in OATP1A2 regulation has been suggested and related to the pathophysiology of breast cancer; therefore, these proteins may be novel therapeutic targets for intervention . Treatment of Caco-2 cells with vitamin D3 markedly increased endogenous OATP1A2 mRNA and protein levels through interaction with the vitamin D receptor (VDR), suggesting that oral dosing of vitamin D3 may modulate intestinal absorption of OATP1A2 substrates [29, 30], although this has not been demonstrated clinically thus far.
5'-AMP-activated protein kinase (AMPK) is another regulator of OATP1A2 expression and function. AMPK has been shown to modulate the subcellular trafficking and stability of OATP1A2. Dysregulation of AMPK signaling is a pathogenetic hallmark of metabolic syndrome, which therefore has a potential impact on the disposition of OATP1A2 drug substrates used for the treatment of patients with this disease .
Xiang et al. identified a putative nuclear factor-κB (NFκB) binding site in the proximal promoter region of SLCO1A2. This transcription factor exerts a repressive effect and may mediate the response of OATP1A2 expression to inflammation .
Altered expression levels and single nucleotide polymorphisms (SNPs) of OATP1A2 are associated with disease states and altered drug disposition. Lee et al. identified and functionally characterized SLCO1A2 SNPs in a population of mixed European, Chinese, Hispanic and African-American descent , and the clinical relevance of SLCO1A2 polymorphisms was more recently reviewed by Zhou et al. . Genotypic frequencies of six non-synonymous polymorphisms within the coding region of SLCO1A2 were dependent on ethnicity, and some of the genetic variants were associated with markedly reduced in vitro uptake transport activity . In vitro studies examining the impact of OATP1A2 polymorphisms and altered pH on the uptake of methotrexate (a substrate of multiple transporters) indicated that OATP1A2 may be important in the toxicity and elimination of this drug . Significant association was found between 550AA genotype and impaired methotrexate disposition . OATP1A2 contributed significantly to doxorubicin uptake in vitro, and polymorphic variants were associated with impaired doxorubicin transport in vitro as well as altered disposition in vivo [36, 37]. OATP1A2 polymorphisms are associated with differences in the pharmacokinetics of imatinib clearance . The SLCO1A2 -189_-188InsA polymorphism was found to be associated with reduced clearance of the neuromuscular blocker rocuronium . Thus, SLCO1A2 polymorphisms may contribute to inter-individual variability in drug disposition and clearance.
The majority of drug interactions on OATP1A2 are ascribed to inhibition of transport in the GIT. Although many OATP-mediated DDIs have been reported  and , these are primarily associated with the basolaterally expressed hepatic transporters OATP1B1 and 1B3, whereas OATP1A2 (and OATP2B1) are expressed at the luminal membrane of enterocytes.
Reported OATP1A2 interactions typically involve dietary components rather than drugs, although tricyclic antidepressants with a short aliphatic amine chain were found to inhibit OATP1A2-mediated rosuvastatin transport . Fruit juices decrease the oral bioavailability of fexofenadine in humans at least in part by inhibition of OATP1A2 [4-6]. Uptake of fexofenadine is inhibited by naringin, a component of grapefruit and orange juice (at 5% soft drink strength) in vitro. In healthy subjects, the AUC of fexofenadine was decreased 25% by ingestion of naringin, and by 40–70% after ingestion of grapefruit or orange juice, consistent with inhibition of OATP1A2 at the apical membrane of enterocytes [4-6, 43]. In another in vivo study with 10 healthy participants, catechins in green tea interfered with the absorption of the beta-blocker nadolol and decreased nadolol plasma exposure by 85% partly through inhibition of OATP1A2 .
Many flavonoids affect OATP-mediated uptake of the model substrates estrone-3-sulphate, estradiol- 17-glucuronide and dehydroepiandrosterone-3-sulphate (DHEAS), suggesting that possible drug–food interactions could occur especially in patients taking over-the-counter dietary supplements in addition to prescribed medications [45, 46]. Other potential drug-food interactions continue to emerge from in vitro investigations (e.g. the Ginkgo flavonoids, apigenin, kaempferol, and quercetin inhibit OATP1A2 and OATP2B1 transport activity , and OATP1A2 transport of the fluoroquinolone antibiotic levofloxacin is inhibited by other quinolones ).
Although the evidence indicates that OATP1A2-mediated oral absorption of some drugs is modified by foods, and that this transporter has broad substrate specificity for important therapeutic drug classes, neither the FDA nor the EMA guidance specifically recommends the study of OATP1A2 interactions for NCEs.
|Location||Endogenous substrates||In vitro substrates used experimentally||Substrate drugs||Inhibitors|
|brain, kidney, liver, intestine||cholic acid, DHEAS
conjugated sex steroids,
linear and cyclic peptides
erythromycin, fexofenadine, imatinib, levofloxacin and other fluoroquinolones, lopinavir, methotrexate, paclitaxel, doxorubicin, fentanyl, rocuronium,
|fruit juices (apple, grapefruit, orange, pomelo)
hesperidins, naringin, rifampicin, rifamycin, verapamil, quinine
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