SLCO4C1 Membrane Protein Introduction

Introduction of SLCO4C1

SLCO4C1 is the first member of the OATP family found to be predominantly expressed in the kidney. SLCO4C1, which is localized in the basolateral membrane of the proximal tubule, plays a major role in the urinary secretion of cardiac glycosides (digoxin and ouabain), thyroid hormones, cAMP, methotrexate, sitagliptin, estrone 3-sulfate, chenodeoxy cholic acid, and glycocholic acid. The OATP family includes sodium-independent organic anion transporters found in various tissues, including liver, kidney, intestine, and brain. OATP transporters facilitate transmembrane transport of bile acids, thyroid hormones, steroid conjugates, anionic oligopeptides, eicosanoids, various drugs, and other xenobiotic compounds. In humans, SLCO4C1 is the only organic anion transporter in the kidney, however, in rodent kidneys, several OATPs are present on the proximal basolateral and apical membranes.

The Function of SLCO4C1 Membrane Protein

In the kidney, SLCO4C1 might be the first step in the transport of digoxin and various compounds into the urine. SLCO4C1 transports thyroid hormone, digoxin, endogenous digoxigenin-like compound, and methotrexate. Many compounds accumulate during renal failure, and kidney-specific SLCO4C1 excretes uremic toxins, resulting in reduced blood pressure and kidney inflammation. Human kidney-specific OATP SLCO4C1 is a molecule responsible for excretion of uremic toxins, and its overexpression in rat kidneys can promote renal excretion of uremic toxins, reduce hypertension, heart hypertrophy and inflammation in renal failure. In addition, SLCO4C1 overexpression can decrease plasma levels of the uremic toxins guanidino succinate, asymmetric dimethylarginine, and the newly identified trans-aconitate. Up-regulation of kidney SLCO4C1 promotes excretion of uremic toxins, reduces kidney inflammation, slows the progression of kidney damage and hemodialysis.

Fig.1 Uremic toxins and SLCO4C1 transporter in renal failure. (Suzuki, 2011)

Application of SLCO4C1 Membrane Protein Literature

1. Suzuki T., et al. Transcriptional regulation of organic anion transporting polypeptide SLCO4C1 as a new therapeutic modality to prevent chronic kidney disease. Journal of Pharmaceutical Sciences. 2011, 100(9): 3696-707. PubMed ID: 21656517
   
   

   This paper demonstrates that SLCO4C1-mediated excretion of uremic toxins and overexpression of human SLCO4C1 in rat kidney promotes renal excretion of uremic toxins and reduces hypertension, cardiac hypertrophy and renal inflammation in renal failure.

2. Toyohara T., et al. SLCO4C1 transporter eliminates uremic toxins and attenuates hypertension and renal inflammation. Journal of the American Society of Nephrology. 2009, 20(12): 2546-55. PubMed ID: 19875811
   
   

   This study finds that drugs that upregulate SLCO4C1 expression may have therapeutic potential for uremic patients.

3. Sato T., et al. Potential drug interactions mediated by renal organic anion transporter OATP4C1. Journal of Pharmacology & Experimental Therapeutics. 2017, 362(2): 271-277. PubMed ID: 28550055
   
   

   This article uses OATP4C1-expressing cells to screen 53 clinically representative drugs to study OATP4C1-mediated drug interactions, providing new insights into the role of OATP4C1 in clinical DDI.

4. Kuo K.L., et al. Localization and Functional Characterization of the Rat Oatp4c1 Transporter in an In Vitro Cell System and Rat Tissues. Plos One. 2012, 7(6): e39641. PubMed ID: 22768102
   
   

   This review reports that rat Oatp4c1 flows to the apical cell surface of polarized epithelium and is predominantly localized to the proximal straight tube.

5. Rodrigues A.D. Endogenous probes for human liver organic anion-transporting polypeptides: the intersection of bioanalytical and ADME science. Bioanalysis. 2018, 10(9): 615-618. PubMed ID: 29768033.
   
   

   This study describes that any combination of the three OATPs (OATP1B1, OATP1B3, and OATP2B1) can serve as an important drug-drug interaction (DDI) target that alters drug pharmacokinetics, toxicity, and efficacy characteristics of the victim.

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Reference

1. Suzuki T, et al. (2011). Transcriptional regulation of organic anion transporting polypeptide SLCO4C1 as a new therapeutic modality to prevent chronic kidney disease. Journal of Pharmaceutical Sciences. 100(9): 3696-707.

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