Oatp1a1 - rat

Oatp1a1 (Organic anion transporting protein 1a1), rat

Aliases: OATP-1, Oatp1, Slc21a1, Slc21a3
Gene name: Solute carrier organic anion transporter, family member 1a1 (Slco1a1)

Summary

rOatp1a1, a sodium-independent bile salt and organic anion transporter, is most abundant in the liver and the kidney, and its substrate range largely overlaps with rOatp1a4 and hOATP1A2. rOatp1a1 has been shown to transport endogenous substances like bile salts, hormones, hormone conjugates, and peptides, and it is thought to be involved in the disposition of drugs and environmental toxins. rOatp1a1 levels are sex- and age-dependent, and react to the diet, drug exposure, and oxidative stress.

Localization

In a Northern blot screen, strongest hybridization signals of rOatp1a1 mRNA were seen in the liver and kidney, with lower signals detected in various organs such as the brain, lung, skeletal muscle, and proximal colon, where the probe was assumed to recognize other Oatp transporters [1]. rOatp1a1 was localized to the apical plasma membrane in kidney proximal tubule cells [2] and in the choroid plexus [3]. In hepatocytes, on the other hand, Oatp1a1 was localized basolaterally. Tissue-dependent membrane domain localization may be explained by differences in processing and trafficking [2, 4].

Function

rOatp1a1 was cloned in 1994 from a liver cDNA library. rOatp1a1 was initially called Oatp1 and renamed only in 2004 when a new species-independent classification and nomenclature system was introduced. This classification is based on amino acid sequence identity; OATPs/Oatps within each family share a minimum of 40% amino acid identity. Human OATP1A2 has five rat and four mouse homologs, all classified into the OATP1A subfamily [5]. 
Oatps are important membrane transport proteins which mediate transport of amphipathic organic compounds including bile salts, hormones and hormone conjugates, peptides, drugs, eicosanoids and toxins in a sodium-independent manner [6]. rOatp1a1 is a sodium-independent bile salt and organic anion transporter with a predicted length of 670 amino acids and a calculated molecular mass of around 74 kDa. The transport mechanism appears to be anion exchange. OATPs/Oatps have 12 transmembrane domains (TM), with a large extracellular loop between TM9 and 10 (extracellular loop 5) containing conserved cysteine residues. The N-glycosylation sites are located on extracellular loops 2 and 5. Conserved amino acids are found in TM domains 2 to 6, in extracellular loops 1, 3, 5 and in intracellular loops 1, 2, 4 and 5 [6]. 
In general, both Oatp1a1 and 1a4 have substrate specificities similar to that of human OATP1A2. The first identified substrates of Oatp1a1 were sulfotaurolithocholate, taurocholate and cholate [1]. Other bile acids like glycocholate, tauroursodeoxycholate and taurochenodeoxycholate were also tested on rOatp1a1, and BSP and taurocholate uptake was inhibited by cholate, chenodeoxycholate, deoxycholate and ursodeoxycholate [7]. rOatp1a1 was able to transport hormones and their conjugates like thyroid hormones [6], aldosterone, cortisol [8], DHEAS [4], and estradiol 17β-D-glucuronide, but not the unconjugated 17β-estradiol. rOatp1a1 preferred steroids with a strong anionic group in the 17- or 3-position, such as estradiol 3-sulfate [9]. Unlike human OATP1A2, rOatp1a1 could also transport opioid peptides [D-Pen2,D-Pen5]-enkephalin and deltorphin II across the blood-brain and blood-cerebrospinal fluid barriers [10, 11].
rOatp1a1 expression is age- and sex-dependent. rOatp1a1 expression was barely detectable at birth and increased with age, but to a differing extent in males and females: after maturation, Oatp1a1 expression was threefold higher in males [12]. High-cholesterol diet [13] and cholestatic and steatotic drugs [14] repressed Oatp1a1 transporter expression in rat hepatocytes; thus, it has been suggested that Oatp1a1 mRNA levels could be utilized in early drug development as a biomarker for the prediction of cholestatic and steatotic side effects [14]. As a contrast, rOatp1a1 expression was upregulated in multiple tissues of hyperuricemic rats treated with Total saponins of Dioscorea (TSD). The treatment successfully reduced uric acid levels in the serum, and the involvement of rOatp1a1 may provide some theoretical foundation for the use of TSD in treating hyperuricemia [15]. Both oxidative stress induced changes in the expression and function of Oatp1a1 and 1a4 in rat hepatocytes, thereby altering pharmacokinetics of their substrates [16]. The activity of rOatp1a1 was found to be regulated by phosphorylation and glycosylation [17, 18]. 

Significance in drug disposition

Oatps are important in drug and toxin disposition. Fexofenadine was transported by both Oatp1a1 and 1a4, albeit with differences in affinity and capacity [19]. rOatp1a1 also mediated rosuvastatin disposition in isolated perfused rat liver, and specific transport of pravastatin by rOatp1a1 was observed in isolated rat hepatocytes, where pravastatin uptake was inhibited by taurocholate and some other statins including lovastatin and simvastatin [20]. In vitro, 100 μM glyburide completely inhibited the uptake of rosuvastatin by all three rat hepatic Oatps (Oatp1a1, 1a4 and 1b2) [21]. In the presence of rifamycin, which inhibits both Oatp1a1 and 1a4, rosuvastatin clearance was reduced, while rifampicin, a specific inhibitor of Oatp1a4 had no effect on drug clearance, indicating that Oatp1a1 (potentially along with other uptake transporters) may contribute to rosuvastatin transport in vivo [22]. Berberine, a plant alkaloid used against hypertension, tumors, and bacterial infections, as well as for its cholesterol-lowering effects, showed accumulation in hepatocytes due to active uptake. Human OATP1B3, as well as rat Oatp1a1, Oatp1a4, and Oatp1b2 all transported this compound, so these transporters seem to participate in the liver disposition and drug-drug interactions of berberine [23]. rOatp1a1 may also influence the renal excretion of drugs and natural toxins. Renal reabsorption of ochratoxin A, a common fungal food contaminant, can be partially inhibited by BSP, which suggests rOatp1a1-mediated transport [4]. Perfluoroalkyl acids (PFAAs), a class of highly degradation-resistant industrial toxicants, have very long serum elimination half-lives in humans. PFAAs are retained via renal reabsorption and the enterohepatic circulation, and multiple OATPs/Oatps (hOATP1B1, hOATP1B3, hOATP2B1, rOatp1a1, rOatp1b2, rOatp2b1 and rOatp1a5) expressed in human and rat hepatocytes and enterocytes have been shown to transport PFAAs [24].

References

1.    Jacquemin, E., et al., Expression cloning of a rat liver Na(+)-independent organic anion transporter. Proc Natl Acad Sci U S A, 1994. 91(1): p. 133-7.
2.    Bergwerk, A.J., et al., Immunologic distribution of an organic anion transport protein in rat liver and kidney. Am J Physiol, 1996. 271(2 Pt 1): p. G231-8.
3.    Angeletti, R.H., et al., The choroid plexus epithelium is the site of the organic anion transport protein in the brain. Proc Natl Acad Sci U S A, 1997. 94(1): p. 283-6.
4.    Eckhardt, U., et al., Polyspecific substrate uptake by the hepatic organic anion transporter Oatp1 in stably transfected CHO cells. Am J Physiol, 1999. 276(4 Pt 1): p. G1037-42.
5.    Hagenbuch, B. and P.J. Meier, Organic anion transporting polypeptides of the OATP/ SLC21 family: phylogenetic classification as OATP/ SLCO superfamily, new nomenclature and molecular/functional properties. Pflugers Arch, 2004. 447(5): p. 653-65.
6.    Hagenbuch, B. and P.J. Meier, The superfamily of organic anion transporting polypeptides. Biochim Biophys Acta, 2003. 1609(1): p. 1-18.
7.    Kullak-Ublick, G.A., et al., Functional characterization of the basolateral rat liver organic anion transporting polypeptide. Hepatology, 1994. 20(2): p. 411-6.
8.    Bossuyt, X., et al., Polyspecific drug and steroid clearance by an organic anion transporter of mammalian liver. J Pharmacol Exp Ther, 1996. 276(3): p. 891-6.
9.    Kanai, N., et al., Estradiol 17 beta-D-glucuronide is a high-affinity substrate for oatp organic anion transporter. Am J Physiol, 1996. 270(2 Pt 2): p. F326-31.
10.    Klaassen, C.D. and L.M. Aleksunes, Xenobiotic, bile acid, and cholesterol transporters: function and regulation. Pharmacol Rev, 2010. 62(1): p. 1-96.
11.    Gao, B., et al., Organic anion-transporting polypeptides mediate transport of opioid peptides across blood-brain barrier. J Pharmacol Exp Ther, 2000. 294(1): p. 73-9.
12.    Hou, W.Y., et al., Age- and sex-related differences of organic anion-transporting polypeptide gene expression in livers of rats. Toxicol Appl Pharmacol, 2014. 280(2): p. 370-7.
13.    Kawase, A., A. Handa, and M. Iwaki, Effects of High-cholesterol Diet on Pravastatin Disposition in the Perfused Rat Liver. Eur J Drug Metab Pharmacokinet, 2017. 42(3): p. 519-526.
14.    Donato, M.T., et al., Both cholestatic and steatotic drugs trigger extensive alterations in the mRNA level of biliary transporters in rat hepatocytes: Application to develop new predictive biomarkers for early drug development. Toxicol Lett, 2016. 263: p. 58-67.
15.    Chen, Y., et al., Total saponins from dioscorea septemloba thunb reduce serum uric acid levels in rats with hyperuricemia through OATP1A1 up-regulation. J Huazhong Univ Sci Technolog Med Sci, 2016. 36(2): p. 237-42.
16.    Tsujimoto, T., et al., Effect of oxidative stress on expression and function of human and rat organic anion transporting polypeptides in the liver. Int J Pharm, 2013.
17.    Glavy, J.S., et al., Down-regulation by extracellular ATP of rat hepatocyte organic anion transport is mediated by serine phosphorylation of oatp1. J Biol Chem, 2000. 275(2): p. 1479-84.
18.    Lee, T.K., et al., N-glycosylation controls functional activity of Oatp1, an organic anion transporter. Am J Physiol Gastrointest Liver Physiol, 2003. 285(2): p. G371-81.
19.    Cvetkovic, M., et al., OATP and P-glycoprotein transporters mediate the cellular uptake and excretion of fexofenadine. Drug Metab Dispos, 1999. 27(8): p. 866-71.
20.    Hsiang, B., et al., A novel human hepatic organic anion transporting polypeptide (OATP2). Identification of a liver-specific human organic anion transporting polypeptide and identification of rat and human hydroxymethylglutaryl-CoA reductase inhibitor transporters. J Biol Chem, 1999. 274(52): p. 37161-8.
21.    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.
22.    Hobbs, M., et al., Understanding the interplay of drug transporters involved in the disposition of rosuvastatin in the isolated perfused rat liver using a physiologically-based pharmacokinetic model. Xenobiotica, 2012. 42(4): p. 327-38.
23.    Chen, C., et al., Organic anion-transporting polypeptides contribute to the hepatic uptake of berberine. Xenobiotica, 2015. 45(12): p. 1138-46.
24.    Zhao, W., et al., Organic Anion Transporting Polypeptides Contribute to the Disposition of Perfluoroalkyl Acids in Humans and Rats. Toxicol Sci, 2016.