Gene name: Solute carrier family 22 member 11 (SLC22A11)
OAT4 is a broad-specificity bidirectional organic anion / dicarboxylate exchanger with endogenous substrates like steroid sulfate conjugates, and xenobiotic substrates including pharmaceutical drugs, phytochemicals, and environmental pollutants. Its cDNA was first isolated from the kidney, and the gene was later also found to be expressed in the placenta, adrenal gland, and salivary gland ducts. The SLC22A11 gene encodes a 550-amino acid, ~70-kDa protein that shares 38 to 44% amino acid sequence identity with other OAT family members. Unlike OAT1 and OAT3 localized to the basolateral membrane of renal proximal tubule cells, OAT4 is positioned apically, and contributes to both the reabsorption and active secretion of its substrates. OAT4 is also a major syncytiotrophoblastic anion transporter involved in the placental uptake of sulfated steroid precursors and other organic anions from the fetal circulation. The current FDA and EMA guidelines contain no recommendations on the in vitro investigation of OAT4 liabilities.
In the kidney, OAT4 is localized on the apical side of proximal tubule cells   , facing the tubular lumen, unlike OATs 1-3, all localized basolaterally. The rank order of OAT expression in the kidney is OAT1 >> OAT3 > OAT4 . In the placenta, OAT4 was observed on the basolateral membrane of the syncytiotrophoblastic layer . This was the first organic anion transporter to be identified in the human placenta, where it is expressed abundantly and plays an important role in the uptake of organic anions from the fetus . The expression of OAT4 along with OAT3 was confirmed by RT-PCR in the adrenal cortex as well as the adrenocortical cell line NCI-H295R . OAT4 expression was also verified in the large intestine and the CaCo2 cell line , and by immunohistochemistry in the salivary gland ducts .
Function, physiology, and clinically significant polymorphisms
The SLC22A11 gene encodes a 550-amino acid, ~70-kDa protein with 12 putative membrane-spanning domains. The protein shares 38 to 44% amino acid sequence identity with other OAT family members. OAT4 is a bidirectional organic anion / dicarboxylate exchanger , albeit OAT4-mediated unidirectional p-aminohippuric acid efflux was also observed . While most studies have confirmed a sodium-independent mode of operation, Ugele et al. have reported partly sodium-dependent transport of estrogens and their precursors . An important class of OAT4 substrates comprises steroid sulfate conjugates, as opposed to glucuronide conjugates which do not interact with OAT4 either as substrates or inhibitors. OAT4 transports estrone 3-sulfate (E3S) and dehydroepiandrosterone sulfate (DHEAS) with high affinity, and DHEAS competes with E3S on OAT4. The sulfate-conjugated metabolite of 17α-ethinylestradiol, a synthetic estrogen receptor agonist, was shown to be taken up from blood into the proximal tubule cells by OAT3 and secreted into the urine by OAT4 . Sulfate conjugates of the flavonoid quercetin  and the isoflavone daidzein  are also OAT4 substrates. The chemically unrelated uric acid is a low-affinity substrate of OAT4, although the transport of E3S versus urate by OAT4 involve different mechanisms . Additionally, OAT4 was found to transport ochratoxin A and, with a low affinity, 6-carboxyfluorescein .
Sulfobromophthalein is a potent inhibitor of OAT4-mediated E3S transport; probenecid, indomethacin, ibuprofen, diclofenac, furosemide, bumetanide, and corticosterone showed modest but dose-dependent inhibition . The inhibitory effect of some angiotensin II receptor antagonists and leukotriene receptor antagonists suggests that OAT4 accepts sulfate, carboxylate and tetrazole groups as an anionic motif .
In the kidney, OAT4 localized to the luminal side of proximal tubules contributes to both the reabsorption and secretion of endogenous substances and xenobiotics . Basolateral OATs and apical OAT4 cooperate in the active secretion of a broad range of substances including antibiotics like cephalosporins and tetracyclines , anticancer drugs like pemetrexed , uremic toxins like indoxyl sulfate , and dietary plant-derived compounds like the sulfate conjugates of hydroxycinnamic acid . While OAT4 contributes to the urinary secretion of the aforementioned substances, other compounds including uric acid and levocetirizine are reabsorbed but not secreted by OAT4 .
In the placenta, OAT4 localized to the basolateral side of the syncytiotrophoblastic layer is one of several transporters involved in the transport of endogenous molecules and xenobiotics through the blood-placenta barrier. As such, OAT4 plays a crucial role in the protection of the fetus from exposure to environmental toxicants like perfluorocarboxylates . Besides its protective and nutritive functions, the placenta is also an active site of steroid hormone synthesis and a major source of elevated estrogen levels in maternal blood . In humans, OATB2B1 and OAT4 are responsible for the placental uptake of steroid hormone precursors. Sulfate-conjugated precursors required for estrogen synthesis, like the fetal liver-derived 16-hydroxy-DHEAS, are imported into the placenta by OAT4 . OAT4 expression in the syncytiotrophoblast was shown to be regulated by protein kinase A, and bromosulfophthalein inhibited estrogen synthesis by blocking OAT4 . For both OAT4 and OATP2B1, glutamate exchange was identified as the dominant driving force for organic anion uptake from the fetal circulation .
The expression of OAT4, along with OAT3, was confirmed in the adrenal cortex; its functional significance is, however, unclear as OAT3 but not OAT4 was shown to be involved in cortisol secretion .
Although naturally occurring exonic variants of OAT4 have no known association with disease, three rare SNPs (L29P, R48Stop, H469R) were demonstrated to display complete loss of function, and common nonsynonymous variants displayed reduced E3S transport. Null mutations caused loss of protein expression and/or plasma membrane localization . The intronic polymorphism rs17300741 showed weak association with renal underexcretion type gout .
Many clinical drugs and toxins interact with OAT4 as substrates, inhibitors, or both. OAT4 was shown to be a target of lesinurad, a selective uric acid reabsorption inhibitor used in combination with xanthine oxidase inhibitors to treat hyperuricemia. Since lesinurad selectively inhibits the apically localized urate transporters URAT1 and OAT4, it has a favorable safety profile in the treatment of gout . The anti-inflammatory drug tranilast also potently reduces serum uric acid levels and causes uricosuria by inhibiting renal urate transporters including OAT4 .
For the cephalosporin antibiotic cephaloridine, OAT4-mediated efflux seems to be the limiting step in clearance, and the accumulation of cephaloridine in proximal tubule cells may cause nephrotoxicity . Similarly, the nephrotoxic phytochemical aristolochic acid can accumulate and cause damage in proximal tubule cells because the affinity of OAT4 to these toxins is 40-fold lower compared to OAT1 and OAT3 .
Although angiotensin II receptor blockers inhibited OAT4-mediated E3S uptake in vitro, this was of no clinical relevance as IC50 values were higher than the therapeutic plasma concentration . On the other hand, some angiotensin II inhibitors are also substrates of OAT4, and OAT4 may contribute to the fetotoxic effect of olmesartan by mediating its transplacental transport .
The current FDA and EMA guidelines contain no recommendations on the in vitro investigation of OAT4 liabilities.
Table: Summary information for OAT4
In vitro substrates used experimentally
DHEAS, E3S, uric acid
DHEAS, E3S, ochratoxin A
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