Human Transporters

OAT7New

OAT7 (organic anion transporter 7)

Alias: UST3

Gene name: Solute carrier family 22 member 9 (SLC22A9)

Summary

Knowledge of the liver-specific human organic anion transporter 7 (OAT7) is very limited. It is expressed exclusively on the sinusoidal (basolateral) side of hepatocytes, where it transports sulfate conjugates of endogenous steroids such as estrone 3-sulfate and dehydroepiandrosterone sulfate, as well as sulfate-conjugated xenobiotics and pravastatin. OAT7-mediated transport is bidirectional, whereby its substrates are exchanged with short chain fatty acids such as butyrate. Unlike other OATs, OAT7 is not inhibited by probenecid, but it interacts with bromosulphthalein. Although OAT7 has been shown to transport pravastatin into hepatocytes in a cyclosporin A-independent manner, it is not currently mentioned in the FDA or EMA guidelines.

Localization

OAT7 was detected in human hepatocytes, but not in the epithelium of bile ducts, blood vessels, or other interstitial tissues of the liver. This transporter is localized at the sinusoidal membrane [1].

Function, physiology, and clinically significant polymorphisms

OAT7 was first described by Shin et al. in 2007 [1]. The amino acid sequence of OAT7 shows 35% to 46% identity with other OAT transporters [1].  The molecular mass of the glycosylated OAT7 protein is approximately 80 kDa; deglycosylation decreases its size to 50-60 kDa [1] [2]. In the liver, OAT7 expression was confirmed by real-time PCR and immunoblot [2] [3]. Using liquid chromatography tandem mass spectrometry (LC-MS/MS), peptide levels of both OAT2 and OAT7 were reliably detectable in hepatocytes, and only minor differences in protein expression were observed across liver tissue samples [4].

The substrate selectivity of OAT7 differs from other OAT transporters since it interacts with sulfate-conjugated xenobiotics and steroid hormones but not with other organic anions or cations. The confirmed OAT2 substrates cGMP, creatinine and ketoprofen are only weak substrates of OAT7, while it transports the steroid sulfates estrone 3-sulfate (E3S) and dehydroepiandrosterone sulfate (DHEAS) with high affinity in a saturable and sodium-independent manner. Trans-stimulation experiments demonstrated that the transporter works as an exchanger. OAT7 mediates a bidirectional transport whereby E3S is exchanged with short chain fatty acids such as butyrate. Pravastatin was previously identified as a substrate of OATs, and OAT7 transports pravastatin as well. However, cyclosporine A, which increased pravastatin serum level by inhibiting OATP1B1, 1B3 and 2B1, had no effect on OAT7-mediated pravastatin uptake [3]. When testing transport activity with p-aminohippuric acid, penciclovir and ganciclovir as substrates, uptake ratios between 2 and 3.6 were observed [5]. OAT7-mediated transport was not inhibited by the otherwise generic OAT inhibitor probenecid [1], although OAT7 was shown to interact with another typical OAT inhibitor bromosulphthalein (BSP). Ketoprofen as an inhibitor demonstrated substrate specificity as it was able to suppress OAT7-mediated E3S and DHEAS transport only [5].

Klein et al. have investigated the regulation of the three liver-specific OATs OAT2, OAT5 and OAT7, and found that HNF-1α (nuclear factor-1α), which regulates a wide variety of hepatocyte-specific genes, transactivated the promoter regions of OAT5 and OAT7 but not of OAT2 [2]. They failed to demonstrate any direct regulatory effect of HNF-4α on the OAT5 or OAT7 promoters. Emami Riedmaier et al., on the other hand, described HNF-4α as a major transcriptional regulator of OAT7 [3]. In the human hepatoma cell line HuH-7 where most SLC transporters are poorly expressed, OAT7 is up-regulated compared to freshly isolated human hepatocytes. Despite the high expression of OAT7 in HuH-7 no transport activity was detectable; hence, HuH-7 could be a model for investigating OAT7 regulation at the posttranscriptional level [6].

The catecholamine epinephrine decreased the expression of various hepatic sinusoidal influx and efflux transporters including OAT7 at the mRNA level, and repressed cytochrome P-450 enzymes. The suppressive effect of epinephrine was detectable in freshly isolated human hepatocytes as well as the HepaRG cell line. Epinephrine was shown to affect transporter expression through the activation of the β2-adrenergic receptor/adenylate cyclase/cAMP pathway [7].

Twenty-four variants in the SLC22A9 gene were reported; six rare heterozygous variants (minor allele frequencies <2%) were detected in a heterozygous form only. Of these, the missense exonic variants p.R90C, p.T433M and p.I479M were cloned by Emami Riedmaier et al., and the transport activity of these variants was determined in overexpressing cell lines. The transport activity of the R90C variant was almost completely abolished, while T433M and I479M were able to transport E3S and pravastatin. The active variants were detected in the plasma membrane, while the non-transporting variant was in located in the cytoplasm.

Regulatory requirements

This transporter is not mentioned in the current FDA or EMA guidelines.

Table: Summary information for OAT7

Location

Endogenous substrates

In vitro substrates used experimentally

Substrate drug

Inhibitors

Liver

E3S, DHEAS

E3S, DHEAS

pravastatin

glutaric acid, BSP, ketoprofen

 

References

[1]        H. J. Shin et al., “Novel Liver-Specific Organic Anion Transporter OAT7 That Operates the Exchange of Sulfate Conjugates for Short Chain Fatty Acid Butyrate,” Hepatology, vol. 45, pp. 1046–1055, 2007, doi: 10.1002/hep.21596.

[2]        K. Klein et al., “The Human Organic Anion Transporter Genes OAT5 and OAT7 Are Transactivated by Hepatocyte Nuclear Factor-1α (HNF-1α),” Mol. Pharmacol., vol. 78, no. 6, pp. 1079–1087, Dec. 2010, doi: 10.1124/mol.110.065201.

[3]        A. Emami Riedmaier et al., “Variability in hepatic expression of organic anion transporter 7/SLC22A9, a novel pravastatin uptake transporter: impact of genetic and regulatory factors,” Pharmacogenomics J., vol. 16, no. 4, pp. 341–351, Aug. 2016, doi: 10.1038/tpj.2015.55.

[4]        A. Vildhede, E. Kimoto, A. D. Rodrigues, and M. V. S. Varma, “Quantification of Hepatic Organic Anion Transport Proteins OAT2 and OAT7 in Human Liver Tissue and Primary Hepatocytes,” Mol. Pharm., vol. 15, no. 8, pp. 3227–3235, Aug. 2018, doi: 10.1021/acs.molpharmaceut.8b00320.

[5]        S. Mathialagan et al., “In vitro studies with two human organic anion transporters: OAT2 and OAT7,” Xenobiotica, vol. 48, no. 10, pp. 1037–1049, Oct. 2018, doi: 10.1080/00498254.2017.1384595.

[6]        E. Jouan, M. Le Vée, C. Denizot, Y. Parmentier, and O. Fardel, “Drug Transporter Expression and Activity in Human Hepatoma HuH-7 Cells,” Pharmaceutics, vol. 9, no. 4, p. 3, Dec. 2016, doi: 10.3390/pharmaceutics9010003.

[7]        A. Mayati, A. Moreau, C. Denizot, B. Stieger, Y. Parmentier, and O. Fardel, “β2-adrenergic receptor-mediated in vitro regulation of human hepatic drug transporter expression by epinephrine,” Eur. J. Pharm. Sci., vol. 106, pp. 302–312, Aug. 2017, doi: 10.1016/j.ejps.2017.06.010.

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