Solute Carrier Protein (SLC) and Drug Transport

Solute Carrier Protein (SLC)
[OATP, OAT and OCT]

OATP

Organic anion transport.
11 known human OATP (SLCO gene name).

(1A2, 1B1, 1B3, 1C1), (2A1, 2B1), 3A1, (4A1, 4C1), 5A1, 6A1.
1B1, 1B3 and 2B1 are expressed on basolateral membrane of hepatocytes while 1A2 expressed primarily on luminal/apical membrane of intestine and in blood-brain barrier.

They possess various SNP variants which affects drug uptake e.g SNPs in 1B1 (691aa) reduce its ability to transport simvastatin acid from circulation to liver.
1B1 and 1B3 expression regulated by HNF1a and HNF3b respectively (Stat5 and IFN-y, HGF, IL-1b mediated activated TFs).

1. Solute Carrier Protein (SLC) [ OATP, OAT and OCT ] Submitted by: Tashvinder Singh PhD Research Scholar Department of Human Genetics and Molecular Medicine Central University of Punjab, Bathinda. [email protected]

2. SLCO Superfamily ( membrane transport protein ) OATP Organic anion transport. 11 known human OATP (SLCO gene name). (1A2, 1B1, 1B3, 1C1), (2A1, 2B1), 3A1, (4A1, 4C1), 5A1, 6A1. 1B1, 1B3 and 2B1 are expressed on basolateral membrane of hepatocytes while 1A2 expressed primarily on luminal/apical membrane of intestine and in blood-brain barrier. They possess various SNP variants which affects drug uptake e.g SNPs in 1B1 (691aa) reduce its ability to transport simvastatin acid from circulation to liver. 1B1 and 1B3 expression regulated by HNF1a and HNF3b respectively (Stat5 and IFN-y, HGF, IL-1b mediated activated TFs).

3. SLCO Superfamily (localisation)

4. SLCO Superfamily

5. OATP1A2 Ubiquitous Meth, Imatinib Naringin, Hesperidin OATP1B1 Liver Methotrexate, Rifampicin Clotrimazole, Gemfibrozil OATP1B3 Liver Digoxin, Docetaxel Cyclo, rifampicin OATP1C1 Brain, Testis Statins Probenecid, DPDPE OATP2A1 Ubiquitous PGs Bromosulphthalein OATP2B1 Ubiquitous Atorvastatin other Cyclosporin, Gemfib OATP3A1 Brain, Testis, Heart, Lung, Spleen Benzylpenicillin - OATP4A1 Heart, Placenta, Lung, Liver Penicillin G,T 3 , T 4 - OATP4C1 Kidney Digoxin, Methotrex - OATP5A1 Breast, Brain, Prostate Gonad specific transports - OATP6A1 Testis, Spleen, Brain, Placenta - -

6. SLCO Superfamily (substrate and inhibitors)

7. SLCO Superfamily (drug-drug interaction)

8. SLC22 Superfamily OAT OAT1-7 and URAT-1 Transport hydrophilic smaller organic anions in exchange with a-ketoglutarate. a-KG gradient maintained by secondary active sodium-dicarboxylate transporters (and then by Na/K ATPases). OAT1 expressed in basolateral membranes of proximal tubules and PM of skeletal muscles. OAT2 in basolateral membranes of proximal tubules and hepatocytes. Strong expression of OAT3 in kidney ( bm of pt ) and lowe in brain. OAT4 present in kidney and placenta (apical membrane of renal proximal tubule). OAT5 and 7 expressed in basolateral membrane of hepatocytes. Strong expression of OAT10 in kidney followed by brain, heart, small intestine, colon. URAT1 is renal specific transporter.

9. SLC22 Superfamily

10. SLC22 Superfamily

11. SLC22 Superfamily

12. SLC22 Superfamily OCT Organic cation transporters; OCT1-3 and organic cation and carnitine transporters; OCT6, OCTN1-2 OCT1 is liver specific transporters (basolateral membrane) along with 1B1 and 1B3 OCT2 is kidney specific transporter (luminal membrane of lung epithelia and DCT) (also in pyramidal cells of cerebral cortex and hippocampus) OCT3, also known as the extraneuronal monoamine transporter (EMT), basolateral membrane of hepatocytes, luminal membrane of lung epithelia. Also present in liver, placenta, kidney and skeletal muscles. OCTN1 present in fetal liver, kidney and lung. Strong expression in kidney trachea and bone marrow. Weak expression in prostate, lung, pancreas, placenta. OCTN2 expressed in apical membranes of proximal tubules. Apical membrane of syncytiotrophoblasts in placenta. Both OCTN1 and 2 present in apical membrane of broncho epithelial cells. OCT6 localised to sertoli cells and epithelial cells of epididymus . Expression seen in hepatocytes and some cancer cell lines.

13. SLC22 Superfamily

14. SLC22 Superfamily

15. SLC22 Superfamily

16. Thank you