Oatp1b2 - rat

Oatp1b2 (organic anion transporting polypeptide 1b2), rat

Aliases: Oatp4, rlst-1, Slc21a10
Gene name: Solute carrier organic anion transporter family member 1b2 (Slco1b2)

Rat Oatp1b2 (Slco1b2) is a sodium-independent transporter selectively expressed in the sinusoidal (basolateral) plasma membrane of hepatocytes [1-3]. As one of the organic anion transporting polypeptides (Oatp/OATP), this transporter is a member of the solute carrier (Slc/SLC) gene family. OATPs mediate the uptake of substrates into hepatocytes as part of the hepatic clearance process. In the rat liver, three types of Oatps (Oatp1a1/Oatp1, Oatp1a4/Oatp2 and Oatp1b2/Oatp4) transport conjugated and unconjugated bile salts and organic anions, and they seem to work together in the absorption and elimination of compounds [1, 4]. Out of these, only Oatp1b2 is liver-specific, and it is expressed at the highest level among the Oatps [5], suggesting that it may play the most important role in the uptake of endogenous and xenobiotic substances from the portal blood into the liver.
A shorter splice variant of Oatp1b2, termed rlst-1, was first reported by Kakyo et al. in 1999 [3]. In 2000, two different groups cloned the full-length rlst-1 [1, 2] which was originally referred to as rlst-1a/Oatp4 and later renamed to Oatp1b2. rOatp1b2 shows 40–44% amino acid homology with rOatp1a1 and rOatp1a4 [1]. The full-length rat Oatp1b2 protein consists of 687 amino acids and has 12 putative transmembrane domains (TMDs), whereas the splice variant rlst-1b lacks one of the 12 TMDs and the third variant rlst-1c features only 10 [2]. Although all variants are expressed, full-length rOatp1b2 is the most important isoform both quantitatively and functionally in the rat liver [4]. Hepatic expression of rOatp1b2 is low in newborns and increases gradually to the adult level during the first few weeks. There is no significant difference in the expression of rOatp1b2 mRNA between sexes [5]. 
rOatp1b2 is a multispecific transporter with high affinities for bromosulfophthalein (BSP), taurocholate, dehydroepiandrosterone 3-sulfate, estrone 3-sulfate, estradiol-17β-glucoronide, T3, T4, cholecystokinin 8 (CCK-8), leukotriene C4, prostaglandin, phalloidin and anionic peptides [1, 4, 6, 7]. It is thought to be the rat counterpart of human OATP1B1 and OATP1B3 since it exhibits 64% and 66% amino acid sequence identity with the human liver-specific OATP1B1 and OATP1B3 transporters, respectively [1, 8]. Rat Oatp1b2 shows high organic anion transport activity comparable to OATP1B1, and shares the ability for peptide transport with OATP1B3 [4]. Like human OATP1Bs, rOatp1b2 was shown to transport statins (rosuvastatin, atorvastatin) and olmesartan [9]. However, only human OATP1B3 transports digoxin [8], and bilirubin, DPDPE, methotrexate and sorafenib are substrates of OATP1B1 and OATP1B3 but not rOatp1b2 [4, 10, 11]. 
Digoxin and rifamycin SV are potent and selective inhibitors of rOatp1b2 and 1a4, while glyburide at 100 µM concentration inhibits all three rat hepatic Oatps [9]. 
Given its high liver-specific expression and broad substrate specificity, rOatp1b2 may play an important role in the formation of the bile. Therefore, learning more about its regulation is expected to improve our understanding of cholestasis [12].

References

1.    Cattori, V., et al., Identification of organic anion transporting polypeptide 4 (Oatp4) as a major full-length isoform of the liver-specific transporter-1 (rlst-1) in rat liver. FEBS Lett, 2000. 474(2-3): p. 242-5.
2.    Choudhuri, S., K. Ogura, and C.D. Klaassen, Cloning of the full-length coding sequence of rat liver-specific organic anion transporter-1 (rlst-1) and a splice variant and partial characterization of the rat lst-1 gene. Biochem Biophys Res Commun, 2000. 274(1): p. 79-86.
3.    Kakyo, M., et al., Molecular characterization and functional regulation of a novel rat liver-specific organic anion transporter rlst-1. Gastroenterology, 1999. 117(4): p. 770-5.
4.    Cattori, V., et al., Localization of organic anion transporting polypeptide 4 (Oatp4) in rat liver and comparison of its substrate specificity with Oatp1, Oatp2 and Oatp3. Pflugers Arch, 2001. 443(2): p. 188-95.
5.    Li, N., et al., Tissue expression, ontogeny, and inducibility of rat organic anion transporting polypeptide 4. J Pharmacol Exp Ther, 2002. 301(2): p. 551-60.
6.    Ismair, M.G., et al., Hepatic uptake of cholecystokinin octapeptide by organic anion-transporting polypeptides OATP4 and OATP8 of rat and human liver. Gastroenterology, 2001. 121(5): p. 1185-90.
7.    Meier-Abt, F., H. Faulstich, and B. Hagenbuch, Identification of phalloidin uptake systems of rat and human liver. Biochim Biophys Acta, 2004. 1664(1): p. 64-9.
8.    Kullak-Ublick, G., et al., Organic anion-transporting polypeptide B (OATP-B) and its functional comparison with three other OATPs of human liver. Gastroenterology, 2001. 120(2): p. 525-33.
9.    Ishida, K., et al., Transport Kinetics, Selective Inhibition, and Successful Prediction of In Vivo Inhibition of Rat Hepatic Organic Anion Transporting Polypeptides. Drug Metab Dispos, 2018. 46(9): p. 1251-1258.
10.    Ma, X., et al., Organic anion transport polypeptide 1b2 selectively affects the pharmacokinetic interaction between paclitaxel and sorafenib in rats. Biochem Pharmacol, 2019. 169: p. 113612.
11.    Hagenbuch, B. and P.J. Meier, The superfamily of organic anion transporting polypeptides. Biochim Biophys Acta, 2003. 1609(1): p. 1-18.
12.    Rost, D., et al., Regulation of rat organic anion transporters in bile salt-induced cholestatic hepatitis: effect of ursodeoxycholate. Hepatology, 2003. 38(1): p. 187-95.