Abcc3 | GeneID:140668 | Rattus norvegicus
[ ] NCBI Entrez Gene
|Gene ID||140668||Official Symbol||Abcc3|
|Full Name||ATP-binding cassette, sub-family C (CFTR/MRP), member 3|
|Description||ATP-binding cassette, sub-family C (CFTR/MRP), member 3|
|Also Known As||multidrug resistance protein 3; organic anion transporter|
|Summary||human homolog transports conjugated metabolites from hepatocytes into the bloodstream; may play a role in steroid metabolism [RGD]|
Orthologs and Paralogs
|GeneID:491084||ABCC3||XP_548204.2||Canis lupus familiaris|
[ ] Monoclonal and Polyclonal Antibodies
|1||sigma||M0318||Anti-MRP3 antibody produced in rabbit ;|
|GO:0016323||Component||basolateral plasma membrane|
|GO:0016021||Component||integral to membrane|
|GO:0005887||Component||integral to plasma membrane|
|GO:0015432||Function||bile acid-exporting ATPase activity|
|GO:0015238||Function||drug transporter activity|
|GO:0008559||Function||xenobiotic-transporting ATPase activity|
|GO:0015722||Process||canalicular bile acid transport|
|GO:0032355||Process||response to estradiol stimulus|
|GO:0032496||Process||response to lipopolysaccharide|
|GO:0014070||Process||response to organic cyclic substance|
|GO:0010243||Process||response to organic nitrogen|
|GO:0010033||Process||response to organic substance|
MicroRNA and Targets
[ ] MicroRNA Sequences and Transcript Targets from miRBase at Sanger
|RNA Target||miRNA #||mat miRNA||Mature miRNA Sequence|
- [ ] Muguruma M, et al. (2008) "Threshold dose of piperonyl butoxide that induces reactive oxygen species-mediated hepatocarcinogenesis in rats." Arch Toxicol. ():. PMID:18648771
- [ ] Petrovic V, et al. (2008) "Effect of endotoxin on the expression of placental drug transporters and glyburide disposition in pregnant rats." Drug Metab Dispos. 36(9):1944-1950. PMID:18505788
- [ ] Merrell MD, et al. (2008) "Induction of drug metabolism enzymes and transporters by oltipraz in rats." J Biochem Mol Toxicol. 22(2):128-135. PMID:18418891
- [ ] Okumura H, et al. (2007) "Change of drug excretory pathway by CCl4-induced liver dysfunction in rat." Biochem Pharmacol. 74(3):488-495. PMID:17544377
- [ ] Ruiz ML, et al. (2006) "Ethynylestradiol increases expression and activity of rat liver MRP3." Drug Metab Dispos. 34(6):1030-1034. PMID:16554369
- [ ] Nishimura M, et al. (2006) "Regulation of mRNA expression of MDR1, MRP1, MRP2 and MRP3 by prototypical microsomal enzyme inducers in primary cultures of human and rat hepatocytes." Drug Metab Pharmacokinet. 21(4):297-307. PMID:16946557
- [ ] Chang TH, et al. (2004) "Expression of MRP2 and MRP3 during liver regeneration after 90% partial hepatectomy in rats." Transplantation. 77(1):22-27. PMID:14724430
- [ ] Tamai M, et al. (2003) "Conjugated bilirubin induces multidrug resistance-associated protein 2 mRNA expression and in vivo cisplatin resistance in rat hepatoma AH66 cells." Anticancer Res. 23(6C):4781-4787. PMID:14981926
- [ ] Li T, et al. (2003) "Transport of fluorescein methotrexate by multidrug resistance-associated protein 3 in IEC-6 cells." Am J Physiol Gastrointest Liver Physiol. 285(3):G602-G610. PMID:12909565
- [ ] Bodo A, et al. (2003) "Differential modulation of the human liver conjugate transporters MRP2 and MRP3 by bile acids and organic anions." J Biol Chem. 278(26):23529-23537. PMID:12704183
- [ ] Akita H, et al. (2002) "Transport activity of human MRP3 expressed in Sf9 cells: comparative studies with rat MRP3." Pharm Res. 19(1):34-41. PMID:11837698
- [ ] Rost D, et al. (2002) "Expression and localization of the multidrug resistance-associated protein 3 in rat small and large intestine." Am J Physiol Gastrointest Liver Physiol. 282(4):G720-G726. PMID:11897632
- [ ] Tzeng SJ, et al. (2002) "Transcriptional regulation of the rat Mrp3 promoter in intestine cells." Biochem Biophys Res Commun. 291(2):270-277. PMID:11846400
- [ ] Ortiz DF, et al. (1999) "MRP3, a new ATP-binding cassette protein localized to the canalicular domain of the hepatocyte." Am J Physiol. 276(6 Pt 1):G1493-G1500. PMID:10362653
- [ ] Hirohashi T, et al. (1998) "Hepatic expression of multidrug resistance-associated protein-like proteins maintained in eisai hyperbilirubinemic rats." Mol Pharmacol. 53(6):1068-1075. PMID:9614210
To determine the threshold dose of piperonyl butoxide (PBO) that induces hepatocellular tumor-promoting effects, reactive oxygen species (ROS) generation, and drug-metabolizing enzymes that protect against ROS generation, partial hepatectomized rats were fed diets containing 0, 0.015, 0.03, 0.06, 0.125, 0.25, or 0.5% PBO after an i.p. injection of N-diethylnitrosamine (DEN) to initiate hepatocarcinogenesis. Histopathologically, Glutathione S-transferase placental form (GST-P)-positive foci were significantly increased in a dose-dependent manner in rats given 0.25% PBO or higher. The formation of microsomal ROS in the liver was significantly increased in 0.25 and 0.5% PBO. Real-time RT-PCR showed that the expression of the CYP1A1, UDPGTr-2, and Mrp3 genes was significantly upregulated in rats given 0.03% PBO or higher. These results suggest that 0.25% is the threshold dose of PBO that induces ROS-mediated hepatocarcinogenesis in rats, although the CYP1A1 gene that is related to ROS generation and the UDPGTr-2 and Mrp3 genes that are involved in protection against ROS were induced in the livers of rats even at a PBO dose of 0.03%.
On average, 80% of pregnant women consume over-the-counter and/or prescription medications. The placenta is a crucial organ that can restrict fetal drug exposure. ATP-binding cassette (ABC) drug transporters play an important role in the placenta because they limit the transplacental transfer of xenobiotics. However, the impact of infection or inflammation on placental drug transporters is not well established. Thus, we examined the impact of endotox-in-induced inflammation on the placental expression of several key drug transporters in rats and its impact on fetal exposure to a drug substrate. Real-time polymerase chain reaction results demonstrated a significant time- and dose-dependent down-regulation of breast cancer resistance protein/Abcg2 mRNA in the placentas of endotoxin-treated rats with a corresponding decrease in protein levels. Likewise, the mRNA levels of several other ABC transporters (Abcb1a, Abcb1b, Abcc1, Abcc2, Abcc3) and members of the organic anion-transporting polypeptides (Slco1a4, Slco2b1, Slco4a1) were down-regulated. A biodistribution study was carried out with glyburide, a hypoglycemic sulfonylurea substrate of both ABC efflux and Oatp uptake transporters. Although administration of endotoxin resulted in comparable plasma concentrations of glyburide, a pronounced increase in the accumulation of glyburide was seen in the fetuses of endotoxin-treated rats (162% of controls, p < 0.01). Glyburide plasma protein binding was not affected by endotoxin treatment. Overall, our results demonstrated a significant reduction in the placental expression of several important drug transporters during endotoxin-induced inflammation. Alterations in glyburide distribution highlight the potential importance of both influx and efflux placental transporters in impacting fetal drug exposure.
Coordinate regulation of Phase-I and -II enzymes with xenobiotic transporters has been shown after treatment with microsomal enzyme inducers. The chemopreventive agent oltipraz (OPZ) induces Phase-I and -II drug-metabolizing enzymes such as CYP2B and NQO1. The purpose of this study was to examine the regulation of drug-metabolizing enzymes and transporters in response to OPZ treatment and to investigate a potential role for constitutive androstane receptor (CAR) in OPZ-mediated induction. Sprague-Dawley rats treated with OPZ exhibited increased mRNA and protein levels of both Nqo1 and Cyp2b1/2 by 24 h. To examine whether OPZ activates transporter gene expression via CAR, sexually dimorphic male and female Wistar-Kyoto (WKY) rats were treated with OPZ and mRNA levels quantified by bDNA signal amplification. OPZ induced Ugt1a6 and Ugt2b1 in males significantly higher than in females, indicating a CAR-dependent mechanism of induction. However, OPZ induced microsomal epoxide hydrolase, NAD(P)H quinone oxidoreductase, and Cyp3a1/23 equally in both genders, indicating a CAR-independent mechanism of induction of these genes. Similarly, the transporters Mdr1a, Mdr1b, Mrp3, and Mrp4 were induced by OPZ without any apparent difference between genders. In summary, OPZ coordinately increases multiple hepatic xenobiotic transporter mRNA levels, along with Phase-I and -II enzymes some of which may occur through CAR-dependent mechanisms.
Liver dysfunction affects the pharmacokinetics of drugs. The liver plays an important role in drug excretion as well as drug metabolism and pharmacokinetics. In the present study, the relationship between changes in the cefmetazole (CMZ) excretory pathway and the degree of liver dysfunction induced by CCl(4) treatment was investigated. CMZ is mainly excreted as an unchanged form in feces in control rats. Depending on the serum levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT), urinary CMZ excretion was increased, whereas fecal CMZ excretion was decreased in rat with liver dysfunction. The AUC of CMZ in rats with severe liver dysfunction was approximately 2-fold higher than that in control rats. Since drug transporters could be involved in drug excretion, changes in the expression of representative hepatic drug transporters in liver dysfunction were investigated by rat DNA microarray. Basolateral solute carrier transporters such as Ntcp, Oct1, and Oatp2 were decreased and basolateral ATP-binding cassette transporters such as Mrp3 and Mrp4 were increased by the CCl(4) treatment. On the other hand, canalicular Mrp2 and Bsep were decreased, but Mdr1 was increased. However, the transporter system for CMZ has not been identified yet. In conclusion, we clarified that the fecal and urinary excretory profiles of CMZ were changed clearly depending on the serum AST and ALT levels in liver dysfunction. The changes in the CMZ excretory pathway might be responsible for the changes in the expression of drug transporters.
We evaluated the effect of ethynylestradiol (EE) administration (5 mg/kg b.wt. s.c., for 5 consecutive days) on the expression and activity of multidrug resistance-associated protein 3 (Mrp3) in rats. Western blotting analysis revealed decreased Mrp2 (-41%) and increased Mrp3 (+200%) expression by EE. To determine the functional impact of up-regulation of Mrp3 versus Mrp2, we measured the excretion of acetaminophen glucuronide (APAP-glu), a common substrate for both transporters, into bile and perfusate in the recirculating isolated perfused liver (IPL) model. APAP-glu was generated endogenously from acetaminophen (APAP), which was administered as a tracer dose (2 micromol/ml) into the perfusate. Biliary excretion of APAP-glu after 60 min of perfusion was reduced in EE-treated rats (-80%). In contrast, excretion into the perfusate was increased by EE (+45%). Liver content of APAP-glu at the end of the experiment was reduced by 36% in the EE group. The total amount of glucuronide remained the same in both groups. Taken together, these results indicate that up-regulation of Mrp3 led to an exacerbated basolateral versus canalicular excretion of conjugated APAP in IPL. We conclude that induced expression of basolateral Mrp3 by EE may represent a compensatory mechanism to prevent intracellular accumulation of common Mrp substrates, either endogenous or exogenous, due to reduced expression and activity of apical Mrp2.
The mRNA induction of various transporters by rifampicin (Rif), dexamethasone (Dex) and omeprazole (Ome) was investigated in primary cultures of cryopreserved human and rat hepatocytes. Analysis was performed by quantitative real-time RT-PCR using primers and TaqMan probes. In primary cultures of human hepatocytes, mRNA levels of MDR and MRP1 were increased by about 1.5 fold and 1.3 fold, respectively, by exposure to Rif at 2 to 50 microM as compared with 0.1% DMSO-treated controls. MRP2 mRNA levels in the same human hepatocytes were significantly increased by 1.2 to 1.8 fold by exposure to Rif at 50 microM as compared with controls. In primary cultures of rat hepatocytes, Mdr1a and Mdr1b mRNA levels were not increased or only slightly increased at 24 hr by exposure to any of the inducers at 2, 10 or 50 microM. Mrp2 mRNA levels in the same rat hepatocytes were significantly increased by 7 to 45 fold by exposure to Dex at 2 microM as compared with controls. Based on the species differences observed in the present study, primary cultures of cryopreserved hepatocytes from both the human and rat should be useful in preclinical drug development for evaluating candidate drugs for transporter induction.
BACKGROUND: Small-for-size grafts often cause persistent conjugated hyperbilirubinemia in the recipient after adult-to-adult living donor liver transplantation, but the cause has not yet been clarified. In physiologic status, bilirubin is excreted from hepatocytes to the bile canaliculus by means of multidrug resistance protein (MRP) 2 and, in particular circumstances, by means of MRP3 to the sinusoidal space. The aim of this study was to research whether there is any change in bilirubin excretion pattern during liver regeneration with reference to expression of MRP2 and MRP3. METHODS: Sprague-Dawley rats underwent sham operation (n=37), 70% hepatectomy (n=38), or 90% hepatectomy (n=37). The degree of liver regeneration, total and direct bilirubin, protein synthesis, and interleukin (IL)-6 were serially assessed. Expression of MRP2 and MRP3 were semiquantified by Western blotting. RESULTS: The proliferating cell nuclear antigen labeling index indicated rapid liver regeneration after 70% and 90% hepatectomy. Serum levels of total and direct bilirubin increased significantly (P<0.05), and conjugated hyperbilirubinemia was proved only in the 90% hepatectomy group. Coagulation factor VII dipped but increased as early as 12 to 24 hr postoperatively in both hepatectomy groups. Plasma IL-6 levels were significantly increased in the 90% hepatectomy group (P<0.05). Expression of MRP2 was decreased and MRP3 was expressed at 36 and 72 hr postoperatively in the 90% hepatectomy group, whereas no change was observed in MRP expression in the 70% hepatectomy group. CONCLUSIONS: During liver regeneration after critical hepatectomy such as 90% hepatectomy, decrease of MRP2 and expression of MRP3 may play an important role in postoperative hyperbilirubinemia.
In vivo cisplatin resistance of rat ascites hepatoma AH66 cells is suggested to result from the induction of multidrug resistance-associated protein 2 (MRP2) expression by ascites fluid (ASF) in the peritoneal cavity. The in vitro cisplatin sensitivity of AH66 cells grown in assay medium containing 5% fetal bovine serum in Dulbecco's modified Eagle's medium (5% FBS DMEM) did not change when the cells were treated with probenecid, an inhibitor of anion transporters, while the decreased cisplatin sensitivity of AH66 cells cultured in an assay medium containing 5% ASF (5% ASF DMEM) was restored by probenecid. Furthermore, in an in vivo study, the survival span (%ILS) of AH66-bearing rats was markedly extended by combination therapy with cisplatin and probenecid, compared with either agent alone. The expression of MRP2 mRNA was increased when AH66 cells were cultured in medium containing 5% ASF or 5% bile for 24 h. The induction of MRP2 mRNA expression in AH66 cells was also observed in the presence of heat-denatured ASF. The bilirubin content in ASF was characteristically higher than that in FBS, normal rat serum or AH66-bearing rat serum. Unconjugated bilirubin did not change the expression of MRP2 mRNA, whereas conjugated bilirubin markedly increased it. The cisplatin uptake in AH66 cells after culture in 5% FBS DMEM containing conjugated bilirubin was about half that of the cells cultured in 5% FBS DMEM alone (p < 0.01). In addition, the cisplatin sensitivity of the cells was significantly lowered by the addition of conjugated bilirubin. The expression of MRP2 mRNA in rat normal hepatocytes was also increased after culture in medium containing 5% ASF or 5% bile. These results indicated that conjugated bilirubin, a component of ASF, induces the mRNA expression of MRP2, which is a determinant of the in vivo cisplatin resistance of AH66 cells.
The transport characteristics of fluorescein methotrexate (F-MTX) were studied by using the rat intestinal crypt cell line IEC-6. Enhanced accumulation of F-MTX at 4 degrees C suggests the existence of an active efflux system. MK-571, an inhibitor of the multidrug resistance-associated protein/ATP binding cassette C (MRP/ABCC) family, also enhanced the accumulation of F-MTX. Transcellular transport of F-MTX from the apical to the basolateral compartment was 2.5 times higher than the opposite direction. This vectorial transport was also reduced by MK-571, indicating the presence of Mrp-type transporter(s) on the basolateral membrane. Mrp3 mRNA was readily detectable, and the protein was localized on the basolateral membrane. Uptake of FMTX into membrane vesicles from IEC-6 cells and Spodoptera frugiperda-9 cells expressing rat Mrp3 were both ATP dependent and saturable as a function of the F-MTX concentration. Similar Km values (11.0 +/- 1.8 and 4.5 +/- 1.1 microM) and inhibition profiles by MK-571, estradiol-17beta-d-glucuronide, and taurocholate for the ATP-dependent transport of F-MTX into these vesicles were obtained. These findings suggest that the efflux of F-MTX is mediated by Mrp3 on the basolateral membrane of IEC-6 cells.
The multidrug resistance proteins MRP2 (ABCC2) and MRP3 (ABCC3) are key primary active transporters involved in anionic conjugate and drug extrusion from the human liver. The major physiological role of MRP2 is to transport conjugated metabolites into the bile canaliculus, whereas MRP3 is localized in the basolateral membrane of the hepatocytes and transports similar metabolites back to the bloodstream. Both proteins were shown to interact with a large variety of transported substrates, and earlier studies suggested that MRPs may work as co-transporters for different molecules. In the present study we expressed the human MRP2 and MRP3 proteins in insect cells and examined their transport and ATPase characteristics in isolated, inside-out membrane vesicles. We found that the primary active transport of estradiol-17-beta-d-glucuronide (E217betaG), a major product of human steroid metabolism, was differently modulated by bile acids and organic anions in the case of human MRP2 and MRP3. Active E217betaG transport by MRP2 was significantly stimulated by the organic anions indomethacin, furosemide, and probenecid and by several conjugated bile acids. In contrast, all of these agents inhibited E217betaG transport by MRP3. We found that in the case of MRP2, ATP-dependent vesicular bile acid transport was increased by E217betaG, and the results indicated an allosteric cross-stimulation, probably a co-transport of bile acids and glucuronate conjugates through this protein. There was no such stimulation of bile acid transport by MRP3. In conclusion, the different transport modulation of MRPs by bile acids and anionic drugs could play a major role in regulating physiological and pathological metabolite fluxes in the human liver.
PURPOSE: Multidrug resistance-associated protein 3 (MRP3) was initially cloned as a hepatic transporter induced under cholestatic/ hyperbilirubinemic conditions. In the present study, transport property of human MRP3 (hMRP3) was compared with that of rat MRP3 (rMRP3). METHODS: Adenosine 5' triphosphate (ATP)-dependent uptake of several organic anions into the membrane vesicles isolated from the Sf9 cells expressing hMRP3 and rMRP3 was measured by rapid filtration technique. RESULTS: ATP-dependent uptake of glucuronide conjugates, glutathione conjugates. and [3H]methotrexate (MTX) was stimulated by infection of cDNAs for hMRP3 and rMRP3. The mean (+/- SE) Km values for the uptake of 17beta estradiol 17beta-D-glucuronide ([3H]E(2)17 betaG) by hMRP3 and rMRP3 were 42.9 +/- 4.3 microM and 33.4 +/- 2.2 microM, respectively. Although the Ki values of glucuronides on the uptake of E217betaG were similar in humans and rats, hMRP3 exhibited higher Ki values toward MTX. In addition, although glycocholate and taurolithocholate 3-sulfate (TLC-S) were transported by both hMRP3 and rMRP3, taurocholate was only transported to a significant degree by rMRP3. Moreover, the inhibitory effect of taurocholate and glycocholate on the transport of E(2)17beta3G was much more potent in rMRP3 compared to hMRP3. CONCLUSION: Collectively, the substrate specificity of hMRP3 resembles that of rMRP3 although differences were observed, particularly in bile acid transport.
Multidrug resistance-associated protein 3 (MRP3; symbol ABCC3), has been shown to mediate ATP-dependent transport of organic anions including 17beta-glucuronosyl estradiol, glucuronosyl bilirubin, monovalent, and sulfated bile salts. MRP3 mRNA expression was reported in rat intestine suggesting a role of MRP3 in the intestinal transport. We examined the expression and localization of MRP3 in rat small and large intestine by RT-PCR, immunofluorescence, and immunoblot analysis. MRP3 was identified in all intestinal segments by RT-PCR. MRP3 expression was low in duodenum and jejunum but markedly increased in ileum and colon. With the use of a rat MRP3 specific antibody, MRP3 was localized to the basolateral domains of enterocytes. Immunofluorescence analysis and immunoblot analysis confirmed a strong expression of rat MRP3 in ileum and colon. In contrast, MRP2 was predominantly expressed in the proximal segments of rat small intestine. Our findings demonstrate a high expression of rat MRP3 in ileum and colon and provide evidence for an involvement of MRP3 in the ATP-dependent transport of organic anions, including bile salts from the enterocyte into blood.
The promoter of rat multidrug resistance protein 3 (Mrp3) has been cloned and analyzed in the rat intestinal cell line (IEC-18 cells). A series of 5' deletion mutants of the Mrp3 promoter region were constructed and placed into the pGL3-Basic vector (luciferase reporter gene). Deletion analysis of the Mrp3 promoter identified a basal transcription element at -123/-106, two negative response regions at -2723/-1128 and -530/-443, respectively, and two positive response regions at -1063/-943 and -302/-157. Further site-directed mutagenesis analysis and gel mobility shift assays provided evidence for Sp1 and Sp3 binding within -123/-105 regions. These studies indicate that Sp1 and Sp3 may be involved in the regulation of the rat Mrp3 gene.
Bile secretion in liver is driven in large part by ATP-binding cassette (ABC)-type proteins that reside in the canalicular membrane and effect ATP-dependent transport of bile acids, phospholipids, and non-bile acid organic anions. Canalicular ABC-type proteins can be classified into two subfamilies based on membrane topology and sequence identity: MDR1, MDR3, and SPGP resemble the multidrug resistance (MDR) P-glycoprotein, whereas MRP2 is similar in structure and sequence to the multidrug resistance protein MRP1 and transports similar substrates. We now report the isolation of the rMRP3 gene from rat liver, which codes for a protein 1522 amino acids in length that exhibits extensive sequence similarity with MRP1 and MRP2. Northern blot analyses indicate that rMRP3 is expressed in lung and intestine of Sprague-Dawley rats as well as in liver of Eisai hyperbilirubinemic rats and TR- mutant rats, which are deficient in MRP2 expression. rMRP3 expression is also transiently induced in liver shortly after birth and during obstructive cholestasis. Antibodies raised against MRP3 recognize a polypeptide of 190-200 kDa, which is reduced in size to 155-165 kDa after treatment with endoglycosidases. Immunoblot analysis and immunoconfocal microscopy indicate that rMRP3 is present in the canalicular membrane, suggesting that it may play a role in bile formation.
The biliary excretion of several organic anions is mediated by the canalicular multispecific organic anion transporter (cMOAT), which is hereditarily defective in mutant rats such as Eisai hyperbilirubinemic rats (EHBR). In addition, using a kinetic study with isolated canalicular membrane vesicles, we recently suggested the presence of ATP-dependent organic anion transporter(s) other than cMOAT in EHBR [Pharm Res (NY) 12:1746-1755 (1995); J Pharmacol Exp Ther 282:866-872 (1997)]. The aim of this study is to provide a molecular basis for the presence of multiplicity in the biliary excretion of organic anions in rats. Based on the homology with human multidrug resistance-associated protein (hMRP), two cDNA fragments encoding the carboxyl-terminal ATP-binding cassette region were amplified by reverse transcription-polymerase chain reaction from EHBR liver. These fragments exhibited approximately 70% amino acid identity with hMRP and rat cMOAT;, therefore, they were designated MRP-like proteins (MLP-1 and MLP-2). The cloned full length cDNA of MLP-1 and -2 from the Sprague-Dawley (SD) rat liver and colon cDNA library was composed of 1502 and 1523 amino acids, respectively, had the characteristics of ATP-binding cassette transporters, and exhibited homology with hMRP and rat cMOAT. Northern blot analysis indicated that MLP-1 is expressed predominantly in the liver in both SD rats and EHBR, whereas hepatic expression of MLP-2 was observed only in EHBR. In addition, MLP-2 was markedly induced by ligation of the bile duct in SD rat liver. In both SD rats and EHBR, MLP-2 was expressed predominantly in the duodenum, jejunum, and colon. These findings suggest that MLP-1 and MLP-2 might be novel members of the MRP family responsible for the excretion of organic anions from these epithelial cells, and that MLP-2 is an inducible one.