OATP2A1 (organic anion transporting polypeptide 2A1)
Aliases: MATR1, PGT, PHOAR2, SLC21A2
Gene name: Solute carrier organic anion transporter family member 2A1 (SLCO2A1)
OATP2A1 is an uptake transporter whose endogenous substrates are prostaglandins, including PGE1, PGE2, PGD2, and PGF2α [1, 2]; thus, it is more traditionally known as the prostaglandin transporter (PGT). Its precise role in PG transport remains unclear. It is ubiquitously expressed, with particularly high mRNA levels in the lung, heart, kidney, and spleen. OATP2A1 is implicated in the release of newly synthesized prostaglandins from cells, in their transepithelial transport, and systemic clearance [3, 4].
OATP2A1 has not been widely reported as a transporter of xenobiotics, although synthetic prostaglandin derivatives (prostanoids, e.g. latanoprost acid) are its substrates, and it may thus be important for the efficacy of this class of drugs. PG transport activity is also modulated by selective and non-selective cyclooxygenase (COX) inhibitors in vitro, and this may be relevant to the gastrointestinal toxicity observed with this class of drugs.
Due to its limited xenobiotic substrate specificity, and no identified DDI risks, neither the FDA nor the EMA guidance makes any recommendation on its evaluation for NCEs.
OATP2A1 is a ubiquitously expressed uptake transporter with particularly high mRNA expression in the lung, heart, kidney and spleen . It was initially cloned from an adult human kidney cDNA library . It is believed to function as an ion exchanger; however (and in common with most OATPs), this has not been fully elucidated. OATP2A1 protein expression was also shown in the upper gastrointestinal tract, namely, the pyloric glands of the antrum, and parietal cells of the gastric corpus . In the human eye, OATP2A1 is expressed predominantly in the choroid/retinal pigment epithelium (RPE) complex and the ciliary body .
Function, physiology, and clinically significant polymorphisms
The broad tissue distribution and the substrate profile of OATP2A1 suggest a key role in the release and distribution of newly synthesized prostaglandins from cells as well as in the metabolic clearance of prostaglandins from the circulation. Prostaglandins are involved in a variety of physiological and pathophysiological processes, and OATP2A1 may play a role in the termination of PGE2 effects by mediating the cellular uptake and subsequent oxidation of prostaglandins in the cytoplasm [5, 8].
A study by Nomura and colleagues  further demonstrated that cellular reuptake is an essential component in the metabolic clearance of prostaglandins. The authors proposed a model where the synthesis, release, reuptake, and oxidation of prostaglandins occur in the same cell in the kidney, but in a compartmentalized manner . However, the nature of compartmentalization is not clearly understood, and it remains to be investigated whether OATP2A1 would have similar functions in other organs.
OATP2A1 is one of a number of OATPs that are highly expressed in cancer . Although it is not a notable drug transporter, some suggest that OATP2A1 could be exploited for chemotherapeutic delivery into e.g. metastatic liver tumors or pancreatic adenocarcinoma [10, 11].
Although no SNPs with relevance to drug disposition have been identified in the SLCO2A1 gene, loss-of-function mutations are causative in rare hereditary diseases. Homozygous or compound heterozygous carriers of some OATP2A1 LOF mutations display CNSU (chronic nonspecific multiple ulcers of the small intestine), an enteropathy characterized by blood and protein loss from the small intestine , while other OATP2A1 mutation carriers present with pachydermoperiostosis (PDP, more recently termed PHOAR2, OMIM #614441), a disease with dermal and skeletal involvement .
The known clinical relevance of OATP2A1 is strongly related to its endogenous function as a prostaglandin transporter.
Various clinically used COX inhibitors have differential impact on PGE2 transport by OATP2A1 in the human stomach, some being inhibitory while others stimulatory. These effects may contribute to the differing gastrointestinal side effects of COX inhibitors .
OATP2A1 is expressed in the choroid/RPE complex and in the ciliary body of the human eye. Prostanoids (e.g. latanoprost), synthetic prostaglandin-F2 (PGF2) derivatives, are the most widely used drugs in glaucoma therapy. They are administered (often as ester pro-drugs) directly onto the cornea, where a small fraction is absorbed into the aqueous humor (AH) and hydrolyzed to the active acid form. Latanoprost acid (the active form) is a potent in vitro substrate and inhibitor of OATP2A1. Experimentation suggests that OATP2A1 and another OATP (2B1) may not only mediate the clearance of the active forms of these drugs from the AH, but may also act as inhibitors of the transporters, thereby decreasing transport of the endogenous substrate and mediating an additional therapeutic benefit by maintaining levels of the endogenous substrate .
Decidualization of human endometrium is a process involving morphological and functional differentiation essential for successful implantation and maintenance of pregnancy. The process of decidualization involves the transformation of fibroblast-like human endometrial stromal cells (ESC) into larger and rounded decidual cells, in preparation for uterine receptivity for the blastocyst. Influx experiments and increased intracellular PG levels in decidual cells strongly suggest that the greater uptake of PG by decidual cells is mediated by OATP2A1, suggesting that OATP2A1 is important in the regulation of PG action in female reproductive processes .
OATP2A1 is overexpressed in various cancers, and as a major determinant of intracellular PGE2 levels it influences prostaglandin-regulated processes such as proliferation and apoptosis, migration and invasion, and epithelial-to-mesenchymal transition . In lung cancer cells, OATP2A1 has been shown to mediate invasion and apoptosis via the PI3K/AKT/mTOR pathway .
As there is no indication that OATP2A1 plays a significant role in the ADME of drugs, neither the FDA nor the EMA guidance makes any recommendation on its evaluation for NCEs.
|Location||Endogenous substrates||In vitro substrates used experimentally||Substrate drugs||Inhibitors|
|ubiquitous||PGE1, PGE2, PGD2, PGF2α, PGH2, thromboxane B2||PGE2||latanoprost and other prostanoids||diclofenac, lumiracoxib, furosemide, DIDs, niflumic acid|
1. Kanai, N., et al., Identification and characterization of a prostaglandin transporter. Science, 1995. 268(5212): p. 866-9.
2. Lu, R., et al., Cloning, in vitro expression, and tissue distribution of a human prostaglandin transporter cDNA(hPGT). Journal of Clinical Investigation, 1996. 98(5): p. 1142-9.
3. Nomura, T., et al., The two-step model of prostaglandin signal termination: in vitro reconstitution with the prostaglandin transporter and prostaglandin 15 dehydrogenase. Molecular Pharmacology, 2004. 65(4): p. 973-8.
4. Nomura, T., et al., Prostaglandin signaling in the renal collecting duct: release, reuptake, and oxidation in the same cell. Journal of Biological Chemistry, 2005. 280(31): p. 28424-9.
5. Schuster, V.L., Prostaglandin transport. Prostaglandins and Other Lipid Mediators, 2002. 68-69: p. 633-47.
6. Mandery, K., et al., Influence of cyclooxygenase inhibitors on the function of the prostaglandin transporter organic anion-transporting polypeptide 2A1 expressed in human gastroduodenal mucosa. Journal of Pharmacology and Experimental Therapeutics, 2010. 332(2): p. 345-51.
7. Kraft, M.E., et al., The prostaglandin transporter OATP2A1 is expressed in human ocular tissues and transports the antiglaucoma prostanoid latanoprost. Investigative Ophthalmology and Visual Science, 2010. 51(5): p. 2504-11.
8. Pitt, B.R., J.R. Forder, and C.N. Gillis, Drug-induced impairment of pulmonary [3H]prostaglandin E1 removal in vivo. Journal of Pharmacology and Experimental Therapeutics, 1983. 227(2): p. 531-7.
9. Kochel, T.J. and A.M. Fulton, Multiple drug resistance-associated protein 4 (MRP4), prostaglandin transporter (PGT), and 15-hydroxyprostaglandin dehydrogenase (15-PGDH) as determinants of PGE2 levels in cancer. Prostaglandins Other Lipid Mediat, 2015. 116-117: p. 99-103.
10. Hays, A., U. Apte, and B. Hagenbuch, Organic anion transporting polypeptides expressed in pancreatic cancer may serve as potential diagnostic markers and therapeutic targets for early stage adenocarcinomas. Pharm Res, 2013. 30(9): p. 2260-9.
11. Wlcek, K., et al., The analysis of organic anion transporting polypeptide (OATP) mRNA and protein patterns in primary and metastatic liver cancer. Cancer Biol Ther, 2011. 11(9): p. 801-11.
12. Umeno, J., et al., A Hereditary Enteropathy Caused by Mutations in the SLCO2A1 Gene, Encoding a Prostaglandin Transporter. PLoS Genet, 2015. 11(11): p. e1005581.
13. Sasaki, T., et al., Identification of mutations in the prostaglandin transporter gene SLCO2A1 and its phenotype-genotype correlation in Japanese patients with pachydermoperiostosis. J Dermatol Sci, 2012. 68(1): p. 36-44.
14. Kang, J., et al., Functional characterization of prostaglandin transporter and terminal prostaglandin synthases during decidualization of human endometrial stromal cells. Human Reproduction, 2006. 21(3): p. 592-9.
15. Zhu, Q., et al., Prostaglandin transporter, SLCO2A1, mediates the invasion and apoptosis of lung cancer cells via PI3K/AKT/mTOR pathway. Int J Clin Exp Pathol, 2015. 8(8): p. 9175-81.