ABCC3

Summary

ABCC3 (ATP binding cassette subfamily C member 3, HGNC:54) is a protein-coding gene on chromosome 17q21.33, encoding ATP-binding cassette sub-family C member 3 (O15438). ATP-dependent transporter of the ATP-binding cassette (ABC) family that binds and hydrolyzes ATP to enable active transport of various substrates including many drugs, toxicants and endogenous compound across cell membranes. In precision oncology, ABCC3 Amplification is associated with resistance to Monomethyl Auristatin E + Paclitaxel in Breast Cancer (CIViC Level D).

The protein encoded by this gene is a member of the superfamily of ATP-binding cassette (ABC) transporters. ABC proteins transport various molecules across extra- and intra-cellular membranes. ABC genes are divided into seven distinct subfamilies (ABC1, MDR/TAP, MRP, ALD, OABP, GCN20, White). This protein is a member of the MRP subfamily which is involved in multi-drug resistance. The specific function of this protein has not yet been determined; however, this protein may play a role in the transport of biliary and intestinal excretion of organic anions. Alternatively spliced variants which encode different protein isoforms have been described; however, not all variants have been fully characterized.

Source: NCBI Gene 8714 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 256 total — 4 pathogenic
• Druggable target: yes — 43 molecules with ChEMBL bioactivity
• Precision-oncology evidence (CIViC): 1 curated variant–drug association
• MANE Select transcript: NM_003786

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:54
Approved symbol	ABCC3
Name	ATP binding cassette subfamily C member 3
Location	17q21.33
Locus type	gene with protein product
Status	Approved
Aliases	MRP3, cMOAT2, EST90757, MLP2, MOAT-D
Ensembl gene	ENSG00000108846
Ensembl biotype	protein_coding
OMIM	604323
Entrez	8714

Gene structure

Transcript identifiers

Ensembl transcripts: 42 — 28 protein_coding, 5 nonsense_mediated_decay, 5 retained_intron, 4 protein_coding_CDS_not_defined

ENST00000285238, ENST00000427699, ENST00000502426, ENST00000503304, ENST00000503337, ENST00000504586, ENST00000505699, ENST00000506464, ENST00000508929, ENST00000510633, ENST00000510891, ENST00000513511, ENST00000513589, ENST00000513745, ENST00000515070, ENST00000515585, ENST00000515707, ENST00000571855, ENST00000871892, ENST00000871893, ENST00000871894, ENST00000871895, ENST00000871896, ENST00000871897, ENST00000871898, ENST00000871899, ENST00000871900, ENST00000871901, ENST00000871902, ENST00000871903, ENST00000871904, ENST00000871905, ENST00000871906, ENST00000871907, ENST00000941182, ENST00000941183, ENST00000941184, ENST00000941185, ENST00000941186, ENST00000941187, ENST00000941188, ENST00000941189

RefSeq mRNA: 2 — MANE Select: NM_003786 NM_001144070, NM_003786

CCDS: CCDS32681, CCDS45739

Canonical transcript exons

ENST00000285238 — 31 exons

Exon	Start	End
ENSE00001109871	50677744	50677943
ENSE00001304270	50678093	50678219
ENSE00002485196	50691092	50692253
ENSE00003462583	50655832	50656008
ENSE00003463288	50667863	50668009
ENSE00003475911	50668853	50668919
ENSE00003480588	50684709	50684875
ENSE00003483060	50675631	50675775
ENSE00003485248	50679798	50679899
ENSE00003498106	50658082	50658207
ENSE00003501788	50667554	50667757
ENSE00003510035	50669352	50669528
ENSE00003528498	50660923	50661114
ENSE00003530296	50675362	50675476
ENSE00003530381	50676278	50676588
ENSE00003531754	50687536	50687730
ENSE00003533551	50683610	50683756
ENSE00003552353	50673469	50673658
ENSE00003552863	50658435	50658496
ENSE00003559764	50657046	50657183
ENSE00003560527	50659237	50659368
ENSE00003588734	50675883	50676090
ENSE00003611947	50683949	50684107
ENSE00003612798	50665153	50665245
ENSE00003615708	50672971	50673138
ENSE00003624124	50668430	50668517
ENSE00003635360	50663681	50663858
ENSE00003639328	50669140	50669266
ENSE00003649077	50656702	50656827
ENSE00003655568	50663950	50664111
ENSE00003842700	50634881	50634981

Expression profiles

Bgee: expression breadth ubiquitous, 231 present calls, max score 99.13.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 17.0387 / max 425.5115, expressed in 1356 samples.

FANTOM5 promoters (10 alternative TSS)

Promoter ID	TPM avg	Samples expressed
161697	15.0663	1282
161694	0.6452	297
161695	0.3560	163
161693	0.2981	159
161696	0.2373	103
161699	0.1429	62
161703	0.1087	48
161704	0.0903	21
208262	0.0887	42
208263	0.0052	1

Top tissues by expression

290 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
pancreatic ductal cell	CL:0002079	99.13	gold quality
right adrenal gland	UBERON:0001233	99.10	gold quality
right adrenal gland cortex	UBERON:0035827	99.01	gold quality
left adrenal gland	UBERON:0001234	98.99	gold quality
left adrenal gland cortex	UBERON:0035825	98.97	gold quality
mucosa of transverse colon	UBERON:0004991	98.82	gold quality
adrenal cortex	UBERON:0001235	98.76	gold quality
right lobe of liver	UBERON:0001114	98.31	gold quality
body of pancreas	UBERON:0001150	97.68	gold quality
adrenal gland	UBERON:0002369	96.47	gold quality
colonic mucosa	UBERON:0000317	96.46	gold quality
gall bladder	UBERON:0002110	96.42	gold quality
rectum	UBERON:0001052	96.16	gold quality
mucosa of sigmoid colon	UBERON:0004993	95.85	gold quality
liver	UBERON:0002107	95.52	gold quality
lower esophagus mucosa	UBERON:0035834	95.47	gold quality
descending thoracic aorta	UBERON:0002345	95.19	gold quality
buccal mucosa cell	CL:0002336	95.00	gold quality
pancreas	UBERON:0001264	94.85	gold quality
ileal mucosa	UBERON:0000331	94.84	gold quality
colonic epithelium	UBERON:0000397	94.61	gold quality
duodenum	UBERON:0002114	94.50	gold quality
body of stomach	UBERON:0001161	94.12	gold quality
pylorus	UBERON:0001166	93.26	gold quality
stomach	UBERON:0000945	92.99	gold quality
transverse colon	UBERON:0001157	92.98	gold quality
mucosa of stomach	UBERON:0001199	92.85	gold quality
thoracic aorta	UBERON:0001515	92.36	gold quality
ascending aorta	UBERON:0001496	92.22	gold quality
small intestine Peyer’s patch	UBERON:0003454	92.19	gold quality

Single-cell (SCXA)

Detected in 8 experiment(s), a significant marker in 8.

Experiment	Marker?	Max mean expression
E-ANND-2	yes	1434.78
E-GEOD-84465	yes	592.71
E-MTAB-5061	yes	26.02
E-MTAB-8410	yes	24.87
E-GEOD-81547	yes	22.15
E-GEOD-125970	yes	16.65
E-ANND-3	yes	12.88
E-HCAD-9	yes	9.77

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AHR, AP1, AR, CEBPB, CEBPG, ESR1, EWSR1, GATA3, HSF4, ID4, IRF6, JUN, KLF12, KMT2A, MTF1, NFE2L2, NR1H4, NR1I2, NR1I3, NR5A2, PLAGL1, PURA, RARA, RXRA, SOX2, SP1, SP3, TCF3, TP53, VDR, WT1, ZNF20

Literature-anchored findings (GeneRIF, showing 40)

• Expression of MRP3 can be induced by certain nonsteroidal anti-inflammatory drugs (e.g., indomethacin) in a reactive oxygen species-dependent but cyclooxygenase-2-independent manner. (PMID:11820781)
• tissue distribution and induction in normal human tissues and in cholestasis (PMID:11850532)
• possible role in the removal of bile acids from the liver in cholestasis (PMID:12220224)
• down- and up-regulation of MRP1 (and MRP3) expression can influence cellular folate homeostasis, in particular when cellular retention by polyglutamylation of folates is attenuated. (PMID:12628490)
• MRP3 active transport of estradiol-17-beta-d-glucuronide and MRP3 ATPase characteristics in isolated, inside-out membrane vesicles (PMID:12704183)
• Genetic polymorphisms in the MRP3 is associated with liver neoplasms (PMID:15167703)
• Upregulation of MRP3 expression is associated with pancreatic carcinoma (PMID:15688370)
• VDR has a role in the protection of colon cells from bile acid toxicity through regulation of the Mrp3 expression (PMID:15824121)
• MRP3, BCRP, and P-glycoprotein have roles in progression of adult acute myeloid leukemia (PMID:16278398)
• a polymorphism -211C>T in the promoter region of MRP3 does not determine the expression level of the gene in acute leukemia (PMID:16424827)
• evidence that clearly indicates that glyburide is preferentially transported by BCRP and MRP3 (PMID:16460798)
• The mRNA induction of MDR1, MRP1, MRP2 and MRP3 by rifampicin (Rif), dexamethasone (Dex) and omeprazole (Ome) was investigated in primary cultures of cryopreserved human and rat hepatocytes. (PMID:16946557)
• our results indicate that activator Sp1 and repressor RXRalpha:RARalpha act in concert to regulate MRP3 expression. loss of RXRalpha:RARalpha may lead to upregulation of MRP3/Mrp3 expression in cholestatic liver injury. (PMID:17272513)
• The ABCC3 -211C>T polymorphism does not affect promotor activity nor FTF transcription factor binding. (PMID:17300812)
• Mrp2 and Mrp3 provide alternative routes for the excretion of a glucuronidated substrate from the liver in vivo. (PMID:17485564)
• MRP1-Pro(1150), MRP2-Pro(1158), and MRP3-Pro(1147) in the cytoplasmic loop 7 differ in their influence on substrate specificity but share a common role in the nucleotide interactions at nucleotide binding domain 2 of these transporters. (PMID:17494643)
• in this study, the 31 ABCC3 exons and their flanking introns were comprehensively screened for genetic variations in 89 Japanese subjects; forty-six genetic variations, including 21 novel ones, were found (PMID:17495421)
• induction of ABCC2 and ABCG2 by tBHQ is mediated by the Nrf2/Keap1 system, whereas the induction of ABCC1 may involve a Keap1-dependent but Nrf2-independent mechanism. (PMID:18038766)
• Polymorphisms in ABCC3 is associated with acute myeloid leukemia (PMID:18207572)
• No significant association was found between the two ABCC3 polymorphisms and colorectal cancer risk. (PMID:18313914)
• ABCC3 is a mediator of taxane resistance in HER2-amplified breast cancer. (PMID:18593940)
• MRP3 could be a novel molecular marker for localized non-mucinous bronchioloalveolar carcinoma, whose expression increases during the early progression of tumourigenesis (PMID:18604784)
• Single nucleotide polymorphisms in the ABCC3 gene is associated with acquisition of hepatotoxicity, due to their poor ability to transport toxic compounds (PMID:18698235)
• the expression of MRP(multiple drug resistance-associated protein)1, MRP2, and MRP3 molecules in systemic lupus erythematosus mononuclear cells was not different from normal (PMID:18799096)
• MRP3, MRP4, and MRP5 are upregulated in 5-fluorouracil-resistant cells, and MRP5 contributes to 5-FU resistance in pancreatic carcinoma cells. (PMID:19077464)
• ABCC3 C-211T and ABCG2 C421A as candidate transporter SNPs to be further investigated as possible predictors of the clinical outcome of chemotherapy in lung cancer patients. (PMID:19107936)
• Vectorial transport of resveratrol metabolites is mediated by multidrug resistance protein 3 (MRP3, ABCC3) located in the basolateral membranes of enterocytes. (PMID:19114588)
• analysis of positive allosteric cooperativity for ABCC3-mediated substrate translocation (PMID:19334674)
• MRP3 induction was dependent upon the transcription factor Nrf2 (PMID:19345732)
• Application of multivariate statistical procedures to identify transcription factors that correlate with MRP2, 3, and 4 mRNA in adult human livers. (PMID:19480556)
• Immunohistochemical evaluation of human gliomas to determine the localization of MRP3 antigen using scFvs M25 and M58 showed a dense cytoplasmic and membranous staining pattern (PMID:19937796)
• MDR1, MRP2, MRP3 and MRP5 levels are decreased by tetramethylpyrazine in human hepatocellular carcinoma cells (PMID:19956884)
• Used a spin-labeled ATP analog, SL-ATP, to study nucleotide binding to highly purified human multidrug resistance protein 3, MRP3. (PMID:20563633)
• study identified genetic polymorphisms of ABCC3 and evaluated their effects on ABCC3 expression and MRP3 function; 61 genetic variants were identified in three ethnic populations; of these variants 17 were novel (PMID:21512263)
• MRP3 A-189 T polymorphism was associated with treatment responses in acute lymphoblastic leukemia , likely due to the change in MRP3 efflux. (PMID:21606946)
• investigation of vectorial transport across enterocytes: Data from Caco-2 cell monolayers, models for intestinal absorption, suggest that MRP3 mediates fexofenadine/zwitterion efflux across basolateral membrane. (PMID:21780830)
• Low ABCC3 expression was associated with reduced event-free survival of neuroblastoma patients. (PMID:21799180)
• effect of ABCB1 and ABCC3 polymorphisms on osteosarcoma survival after chemotherapy (PMID:22016816)
• We demonstrate direct involvement between nuclear factor erythroid-2-related factor 2 and the MRP3 promoter, which leads to the up-regulation of the MRP3 gene. (PMID:22089114)
• up-regulation of hepatic MRP3/ABCC3 expression in human obstructive cholestasis is likely triggered by TNFalpha, mediated by activation of JNK/SAPK and SP1. (PMID:22105759)

Cross-species orthologs

15 orthologs

Organism	Symbol	Gene ID
mus_musculus	Abcc3	ENSMUSG00000020865
rattus_norvegicus	Abcc3	ENSRNOG00000002948
drosophila_melanogaster	l(2)03659	FBGN0010549
drosophila_melanogaster	CG7627	FBGN0032026
drosophila_melanogaster	MRP	FBGN0032456
drosophila_melanogaster	CG9270	FBGN0032908
drosophila_melanogaster	CG10505	FBGN0034612
drosophila_melanogaster	Mrp5	FBGN0038740
drosophila_melanogaster	rdog	FBGN0039644
drosophila_melanogaster	CG11898	FBGN0039645
drosophila_melanogaster	CG31792	FBGN0051792
drosophila_melanogaster	CG31793	FBGN0051793
drosophila_melanogaster	Mrp4	FBGN0263316
caenorhabditis_elegans		WBGENE00000477
caenorhabditis_elegans		WBGENE00003413

Paralogs (11): CFTR (ENSG00000001626), ABCC8 (ENSG00000006071), ABCC2 (ENSG00000023839), ABCC9 (ENSG00000069431), ABCC6 (ENSG00000091262), ABCC1 (ENSG00000103222), ABCC5 (ENSG00000114770), ABCC11 (ENSG00000121270), ABCC10 (ENSG00000124574), ABCC4 (ENSG00000125257), ABCC12 (ENSG00000140798)

Protein

Protein identifiers

ATP-binding cassette sub-family C member 3 — O15438 (reviewed: O15438)

Alternative names: Canalicular multispecific organic anion transporter 2, Multi-specific organic anion transporter D, Multidrug resistance-associated protein 3

All UniProt accessions (6): O15438, D6RAB7, D6RJE5, H0Y8Q6, H0Y8T5, H0Y9T4

UniProt curated annotations — full annotation on UniProt →

Function. ATP-dependent transporter of the ATP-binding cassette (ABC) family that binds and hydrolyzes ATP to enable active transport of various substrates including many drugs, toxicants and endogenous compound across cell membranes. Transports glucuronide conjugates such as bilirubin diglucuronide, estradiol-17-beta-o-glucuronide and GSH conjugates such as leukotriene C4 (LTC4). Transports also various bile salts (taurocholate, glycocholate, taurochenodeoxycholate-3-sulfate, taurolithocholate- 3-sulfate). Does not contribute substantially to bile salt physiology but provides an alternative route for the export of bile acids and glucuronides from cholestatic hepatocytes. May contribute to regulate the transport of organic compounds in testes across the blood-testis-barrier. Can confer resistance to various anticancer drugs, methotrexate, tenoposide and etoposide, by decreasing accumulation of these drugs in cells.

Subcellular location. Basolateral cell membrane. Basal cell membrane.

Tissue specificity. Mainly expressed in the liver. Also expressed in small intestine, colon, prostate, testis, brain and at a lower level in the kidney. In testis, localized to peritubular myoid cells, Leydig cells, along the basal membrane of Sertoli cells and moderately in the adluminal compartment of the seminiferous tubules.

Induction. Strongly up-regulated under conditions of MRP2 deficiency.

Miscellaneous. May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay. May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay. May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay.

Similarity. Belongs to the ABC transporter superfamily. ABCC family. Conjugate transporter (TC 3.A.1.208) subfamily.

Isoforms (5)

UniProt ID	Names	Canonical?
O15438-1	1, MRP3	yes
O15438-2	2, MRP3A
O15438-3	3, MRP3B
O15438-4	4, MRP3S1
O15438-5	5

RefSeq proteins (2): NP_001137542, NP_003777* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003439	ABC_transporter-like_ATP-bd	Domain
IPR003593	AAA+_ATPase	Domain
IPR005292	MRP	Family
IPR011527	ABC1_TM_dom	Domain
IPR017871	ABC_transporter-like_CS	Conserved_site
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR036640	ABC1_TM_sf	Homologous_superfamily
IPR050173	ABC_transporter_C-like	Family
IPR056227	TMD0_ABC	Domain

Pfam: PF00005, PF00664, PF24357

Enzyme classification (BRENDA):

• EC 7.6.2.3 — ABC-type glutathione-S-conjugate transporter (BRENDA: 8 organisms, 145 substrates, 63 inhibitors, 16 Km, 0 kcat entries)

Substrate kinetics (BRENDA)

7 substrates with measured Km, best-characterized 7. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
ATP	0.0865–0.91	5
MONOMETHYLARSONOUS ACID DIGLUTATHIONE[SIDE 1]	0.023–0.033	4
S-(2,4-DINITROPHENYL)GLUTATHIONE[SIDE 1]	0.0141–0.032	2
S-(LEUKOTRIENE C4)GLUTATHIONE[SIDE 1]	0.0001	2
4-(GLUTATHIONE-S-YL)-QUINOLINE-1-OXIDE[SIDE 1]	0.0095	1
ARSENIC TRIGLUTATHIONE[SIDE 1]	0.0003	1
S-GLUTATHIONE[SIDE 1]	12	1

Catalyzed reactions (Rhea), 10 shown:

• an S-substituted glutathione(in) + ATP + H2O = an S-substituted glutathione(out) + ADP + phosphate + H(+) (RHEA:19121)
• leukotriene C4(in) + ATP + H2O = leukotriene C4(out) + ADP + phosphate + H(+) (RHEA:38963)
• taurocholate(in) + ATP + H2O = taurocholate(out) + ADP + phosphate + H(+) (RHEA:50052)
• glycocholate(in) + ATP + H2O = glycocholate(out) + ADP + phosphate + H(+) (RHEA:50056)
• taurolithocholate 3-sulfate(in) + ATP + H2O = taurolithocholate 3-sulfate(out) + ADP + phosphate + H(+) (RHEA:50084)
• 17beta-estradiol 17-O-(beta-D-glucuronate)(in) + ATP + H2O = 17beta-estradiol 17-O-(beta-D-glucuronate)(out) + ADP + phosphate + H(+) (RHEA:60128)
• dehydroepiandrosterone 3-sulfate(in) + ATP + H2O = dehydroepiandrosterone 3-sulfate(out) + ADP + phosphate + H(+) (RHEA:61364)
• taurochenodeoxycholate 3-sulfate(in) + ATP + H2O = taurochenodeoxycholate 3-sulfate(out) + ADP + phosphate + H(+) (RHEA:66176)
• (4Z,15Z)-bilirubin IXalpha C8-beta-D-glucuronoside(in) + ATP + H2O = (4Z,15Z)-bilirubin IXalpha C8-beta-D-glucuronoside(out) + ADP + phosphate + H(+) (RHEA:66180)
• (4Z,15Z)-bilirubin IXalpha C8,C12-beta-D-bisglucuronoside(in) + ATP + H2O = (4Z,15Z)-bilirubin IXalpha C8,C12-beta-D-bisglucuronoside(out) + ADP + phosphate + H(+) (RHEA:66192)

UniProt features (212 total): helix 77, strand 32, turn 29, topological domain 18, transmembrane region 17, sequence conflict 13, sequence variant 7, splice variant 6, domain 4, glycosylation site 3, binding site 2, modified residue 2, chain 1, region of interest 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
8HVH	ELECTRON MICROSCOPY	3.07
8IZP	ELECTRON MICROSCOPY	3.31
8HW4	ELECTRON MICROSCOPY	3.52
8HW2	ELECTRON MICROSCOPY	3.65

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O15438-F1	82.29	0.39

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Ligand- & substrate-binding residues (2): 661–668; 1323–1330

Post-translational modifications (2): 908, 911

Glycosylation sites (3): 18, 1006, 1007

Function

Pathways and Gene Ontology

Reactome pathways

16 pathways

ID	Pathway
R-HSA-159418	Recycling of bile acids and salts
R-HSA-382556	ABC-family protein mediated transport
R-HSA-9749641	Aspirin ADME
R-HSA-9753281	Paracetamol ADME
R-HSA-9818032	NFE2L2 regulating MDR associated enzymes
R-HSA-1430728	Metabolism
R-HSA-194068	Bile acid and bile salt metabolism
R-HSA-2262752	Cellular responses to stress
R-HSA-382551	Transport of small molecules
R-HSA-556833	Metabolism of lipids
R-HSA-8953897	Cellular responses to stimuli
R-HSA-8957322	Metabolism of steroids
R-HSA-9711123	Cellular response to chemical stress
R-HSA-9748784	Drug ADME
R-HSA-9755511	KEAP1-NFE2L2 pathway
R-HSA-9759194	Nuclear events mediated by NFE2L2

MSigDB gene sets: 294 (showing top): WANG_CLIM2_TARGETS_UP, BENPORATH_ES_WITH_H3K27ME3, GOBP_CIRCULATORY_SYSTEM_PROCESS, JAEGER_METASTASIS_DN, MCBRYAN_PUBERTAL_TGFB1_TARGETS_DN, GOBP_XENOBIOTIC_TRANSMEMBRANE_TRANSPORT, GOBP_ORGANIC_ACID_TRANSPORT, KEGG_ABC_TRANSPORTERS, GOBP_ORGANIC_HYDROXY_COMPOUND_TRANSPORT, SENESE_HDAC1_AND_HDAC2_TARGETS_DN, PICCALUGA_ANGIOIMMUNOBLASTIC_LYMPHOMA_UP, FONTAINE_PAPILLARY_THYROID_CARCINOMA_UP, MCBRYAN_PUBERTAL_BREAST_3_4WK_UP, GOBP_ORGANIC_ANION_TRANSPORT, MODULE_71

GO Biological Process (11): xenobiotic metabolic process (GO:0006805), xenobiotic transmembrane transport (GO:0006855), bile acid and bile salt transport (GO:0015721), xenobiotic transport (GO:0042908), transmembrane transport (GO:0055085), leukotriene transport (GO:0071716), transport across blood-brain barrier (GO:0150104), lipid transport (GO:0006869), glucuronoside transport (GO:0015779), carboxylic acid transport (GO:0046942), monoatomic anion transmembrane transport (GO:0098656)

GO Molecular Function (13): ATP binding (GO:0005524), ABC-type xenobiotic transporter activity (GO:0008559), glucuronoside transmembrane transporter activity (GO:0015164), ABC-type glutathione S-conjugate transporter activity (GO:0015431), ABC-type bile acid transporter activity (GO:0015432), ATP hydrolysis activity (GO:0016887), ATPase-coupled transmembrane transporter activity (GO:0042626), xenobiotic transmembrane transporter activity (GO:0042910), obsolete ATPase-coupled inorganic anion transmembrane transporter activity (GO:0043225), icosanoid transmembrane transporter activity (GO:0071714), ABC-type transporter activity (GO:0140359), nucleotide binding (GO:0000166), transmembrane transporter activity (GO:0022857)

GO Cellular Component (5): plasma membrane (GO:0005886), basal plasma membrane (GO:0009925), basolateral plasma membrane (GO:0016323), ciliary basal body (GO:0036064), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-11 pathways:

Category	Pathways
Drug ADME	2
Bile acid and bile salt metabolism	1
Transport of small molecules	1
Nuclear events mediated by NFE2L2	1
Metabolism of steroids	1
Cellular responses to stimuli	1
Metabolism	1
Metabolism of lipids	1
Cellular responses to stress	1
Cellular response to chemical stress	1
KEAP1-NFE2L2 pathway	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
transport	3
ABC-type transporter activity	3
xenobiotic transport	2
transmembrane transport	2
icosanoid transport	2
ATP-dependent activity	2
plasma membrane region	2
metabolic process	1
cellular response to xenobiotic stimulus	1
lipid transport	1
monocarboxylic acid transport	1
organic hydroxy compound transport	1
cellular process	1
vascular transport	1
lipid localization	1
glycoside transport	1
organic acid transport	1
monoatomic anion transport	1
monoatomic ion transmembrane transport	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
xenobiotic transmembrane transporter activity	1
glucuronoside transport	1
carbohydrate derivative transmembrane transporter activity	1
sulfur compound transmembrane transporter activity	1
bile acid transmembrane transporter activity	1
ATPase-coupled carboxylic acid transmembrane transporter activity	1
ATPase-coupled lipid transmembrane transporter activity	1
ribonucleoside triphosphate phosphatase activity	1
primary active transmembrane transporter activity	1
ATP hydrolysis activity	1
transmembrane transporter activity	1
lipid transmembrane transporter activity	1
ATPase-coupled transmembrane transporter activity	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
transporter activity	1
membrane	1
cell periphery	1
basal part of cell	1

Protein interactions and networks

STRING

1890 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ABCC3	SLC51A	Q86UW1	907
ABCC3	SLC51B	Q86UW2	808
ABCC3	MRPS7	Q9Y2R9	769
ABCC3	CYP7A1	P22680	769
ABCC3	SLCO1B1	Q9Y6L6	765
ABCC3	SLC10A1	Q14973	733
ABCC3	SLCO1B3	Q9NPD5	724
ABCC3	SLCO1A2	P46721	721
ABCC3	SLCO2B1	O94956	713
ABCC3	NR1I2	O75469	709
ABCC3	NUP93	Q8N1F7	684
ABCC3	FGF19	O95750	641
ABCC3	SLC22A7	Q9Y694	635
ABCC3	ABCG2	Q9UNQ0	626
ABCC3	SLC22A1	O15245	611

IntAct

11 interactions, top by confidence:

A	B	Type	Score
EGFR	NDUFA4	psi-mi:“MI:0914”(association)	0.530
ABCC3	MLH1	psi-mi:“MI:0915”(physical association)	0.370
PA	ESYT2	psi-mi:“MI:0914”(association)	0.350
NTRK1	ILVBL	psi-mi:“MI:0914”(association)	0.350
CRELD1	TMEM223	psi-mi:“MI:0914”(association)	0.350
KLHL22	TRAV18	psi-mi:“MI:0914”(association)	0.350
ABCC3		psi-mi:“MI:0915”(physical association)	0.000
ABCC3	ubiF	psi-mi:“MI:0915”(physical association)	0.000
ABCC3	tadA	psi-mi:“MI:0915”(physical association)	0.000
	ABCC3	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (36): ABCC3 (Co-fractionation), ABCC3 (Co-fractionation), ABCC3 (Co-fractionation), ABCC3 (Co-fractionation), EEF2 (Co-fractionation), VDAC1 (Co-fractionation), VDAC2 (Co-fractionation), VDAC3 (Co-fractionation), ABCC3 (Affinity Capture-MS), ABCC3 (Proximity Label-MS), ABCC3 (Protein-RNA), ABCC3 (Proximity Label-MS), ABCC3 (Proximity Label-MS), ABCC3 (Proximity Label-MS), ABCC3 (Proximity Label-MS)

ESM2 similar proteins: A0A0G2K1Q8, B2RX12, E9PU17, E9PX95, F1MWM0, O00329, O15438, O35600, O75899, O88563, O88871, O94911, O95477, P41233, P55205, P58428, P78363, Q09427, Q09428, Q09429, Q2NKY8, Q5BJS0, Q5R607, Q5ZI74, Q6TL19, Q7L2E3, Q7TNJ2, Q80T41, Q84M24, Q8CF82, Q8IUA7, Q8K440, Q8K441, Q8K442, Q8K448, Q8K449, Q8LPK0, Q8N139, Q8NCL4, Q8R420

Diamond homologs: A0A0D1CZ63, A0A0U1LQE1, A0A1U8QTJ9, A2XCD4, A7KVC2, B2RX12, E9Q236, F1M3J4, F9X9V4, G4N2B5, J9VQH1, O15438, O15439, O15440, O31708, O35379, O60706, O70127, O88269, O88563, O95255, P0CE69, P14772, P16875, P16877, P21439, P21440, P32386, P33527, P38735, P39109, P53049, P70170, P82451, P91660, P9WEL8, Q07QX6, Q08201, Q09427, Q0VQP5

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
SOX2	“up-regulates quantity by expression”	ABCC3	“transcriptional regulation”

Disease & clinical

Cancer significance

Clinical variants and AI predictions

ClinVar

256 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	4
Likely pathogenic	0
Uncertain significance	177
Likely benign	29
Benign	5

Top pathogenic / likely-pathogenic (4)

Variant ID	HGVS	Classification
2692407	Single allele	Pathogenic
3242218	Single allele	Pathogenic
59589	GRCh38/hg38 17q21.32-22(chr17:49137864-52147810)x1	Pathogenic
59590	GRCh38/hg38 17q21.33-22(chr17:49974533-56807609)x1	Pathogenic

SpliceAI

5512 predictions. Top by Δscore:

Variant	Effect	Δscore
17:50634980:GG:G	donor_gain	1.0000
17:50634980:GGGTA:G	donor_loss	1.0000
17:50634981:GG:G	donor_gain	1.0000
17:50634982:G:GA	donor_loss	1.0000
17:50634982:G:GG	donor_gain	1.0000
17:50655827:CCCA:C	acceptor_loss	1.0000
17:50655829:CA:C	acceptor_loss	1.0000
17:50655830:A:AG	acceptor_gain	1.0000
17:50655830:A:G	acceptor_loss	1.0000
17:50655831:G:GA	acceptor_loss	1.0000
17:50655831:G:GG	acceptor_gain	1.0000
17:50656005:GATG:G	donor_gain	1.0000
17:50656009:G:GG	donor_gain	1.0000
17:50657179:CAGAG:C	donor_loss	1.0000
17:50657180:AGAG:A	donor_loss	1.0000
17:50657185:T:A	donor_loss	1.0000
17:50658208:G:GG	donor_gain	1.0000
17:50658497:G:GG	donor_gain	1.0000
17:50658902:G:GT	donor_gain	1.0000
17:50659345:G:GT	donor_gain	1.0000
17:50659365:CACGG:C	donor_loss	1.0000
17:50659367:CGGTG:C	donor_loss	1.0000
17:50659368:GGTG:G	donor_loss	1.0000
17:50659369:GT:G	donor_loss	1.0000
17:50659370:T:A	donor_loss	1.0000
17:50660915:T:TA	acceptor_gain	1.0000
17:50660916:G:A	acceptor_gain	1.0000
17:50661080:G:GT	donor_gain	1.0000
17:50663855:G:GT	donor_gain	1.0000
17:50663856:A:T	donor_gain	1.0000

AlphaMissense

9915 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:50687607:A:T	E1451V	0.998
17:50687607:A:C	E1451A	0.997
17:50687607:A:G	E1451G	0.997
17:50687608:G:C	E1451D	0.997
17:50687608:G:T	E1451D	0.997
17:50687699:C:G	H1482D	0.997
17:50673011:T:C	L761P	0.996
17:50687604:A:T	D1450V	0.996
17:50687606:G:A	E1451K	0.996
17:50687703:G:C	R1483P	0.996
17:50669382:T:A	W699R	0.995
17:50669382:T:C	W699R	0.995
17:50683973:G:C	A1327P	0.995
17:50683980:A:T	K1329M	0.995
17:50684107:G:C	Q1371H	0.995
17:50684107:G:T	Q1371H	0.995
17:50687553:T:C	L1433P	0.995
17:50687604:A:C	D1450A	0.995
17:50687606:G:C	E1451Q	0.995
17:50687615:G:C	A1454P	0.995
17:50687701:C:A	H1482Q	0.995
17:50687701:C:G	H1482Q	0.995
17:50673007:A:C	S760R	0.994
17:50673009:T:A	S760R	0.994
17:50673009:T:G	S760R	0.994
17:50683977:G:A	G1328D	0.994
17:50683979:A:C	K1329Q	0.994
17:50683981:G:C	K1329N	0.994
17:50683981:G:T	K1329N	0.994
17:50683983:C:T	S1330F	0.994

dbSNP variants (sampled 300 via entrez): RS1000017617 (17:50669867 G>A), RS1000035374 (17:50634916 T>C), RS1000088582 (17:50661968 A>G), RS1000164889 (17:50653358 A>G), RS1000192556 (17:50643864 C>T), RS1000265755 (17:50637686 C>T), RS1000341256 (17:50679095 T>A,C,G), RS1000364464 (17:50667982 G>A), RS1000440748 (17:50673834 G>A), RS1000498620 (17:50683289 G>A,T), RS1000541529 (17:50642164 G>A), RS1000604175 (17:50658566 G>A), RS1000705409 (17:50677626 C>T), RS1000720535 (17:50692387 G>C), RS1000775943 (17:50678906 C>T)

Disease associations

OMIM: gene MIM:604323 | disease phenotypes: MIM:166200, MIM:190320, MIM:604370

GenCC curated gene-disease

Mondo (3): osteogenesis imperfecta type 1 (MONDO:0008146), tricho-dento-osseous syndrome (MONDO:0008592), breast-ovarian cancer, familial, susceptibility to, 1 (MONDO:0011450)

Orphanet (4): Osteogenesis imperfecta type 1 (Orphanet:216796), Tricho-dento-osseous syndrome (Orphanet:3352), Osteogenesis imperfecta (Orphanet:666), Hereditary breast and/or ovarian cancer syndrome (Orphanet:145)

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

0 associations (top):

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C536549	Tricho-dento-osseous syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5918 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

43 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 740,801 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1017	TELMISARTAN	4	27,457
CHEMBL1096885	VALRUBICIN	4	41,463
CHEMBL114	SAQUINAVIR	4	39,899
CHEMBL1200692	OLMESARTAN MEDOXOMIL	4	17,268
CHEMBL1200865	LOTEPREDNOL ETABONATE	4	11,414
CHEMBL1201182	TEMSIROLIMUS	4	25,195
CHEMBL1272	REPAGLINIDE	4	33,453
CHEMBL1292	CLOFAZIMINE	4	15,481
CHEMBL1324	TOLCAPONE	4	13,819
CHEMBL1370	BUDESONIDE	4	72,936
CHEMBL1481	GLIMEPIRIDE	4	33,335
CHEMBL1513	IRBESARTAN	4	31,667
CHEMBL160	CYCLOSPORINE	4	168,247
CHEMBL1617	RIFAXIMIN	4	13,380
CHEMBL163	RITONAVIR	4	53,773
CHEMBL1660	RIFAPENTINE	4	12,680
CHEMBL1744447	ROSUVASTATIN CALCIUM	4	418
CHEMBL1908360	EVEROLIMUS	4	73,430
CHEMBL2103772	RACECADOTRIL	4	1,787
CHEMBL2220442	FLUVASTATIN	4	53,699
CHEMBL282724	SITAXENTAN	4
CHEMBL308954	ETRAVIRINE	4
CHEMBL3140361	ETHAMBUTOL HYDROCHLORIDE	4
CHEMBL374478	RIFAMPIN	4
CHEMBL393220	ATORVASTATIN CALCIUM	4
CHEMBL408	TROGLITAZONE	4
CHEMBL421	SULFASALAZINE	4
CHEMBL452231	TENIPOSIDE	4
CHEMBL456	ETHACRYNIC ACID	4
CHEMBL472	GLYBURIDE	4

Clinical evidence (CIViC)

Drug × variant × indication: 1 predictive associations from 1 curated evidence items.

Variant	Therapy	Indication	Effect	Level	CIViC
ABCC3 Amplification	Monomethyl Auristatin E + Paclitaxel	Breast Cancer	Resistance	CIViC D	EID951

PharmGKB: 1 entry (VIP=true, CPIC=false)

PharmGKB clinical annotations

4 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs1051640	Toxicity	3	cisplatin	Drug Toxicity;Neoplasms;Ototoxicity
rs4148416	Efficacy	3	cisplatin;cyclophosphamide;doxorubicin;methotrexate;vincristine	Osteosarcoma
rs4793665	Other	3	morphine	Pain
rs9895420	Efficacy	3	methotrexate	Acute lymphoblastic leukemia

PharmGKB variants

15 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs1051640	ABCC3	3	2.00	1	cisplatin
rs4148405	ABCC3		0.00	0
rs4148416	ABCC3	3	1.50	1	cisplatin;cyclophosphamide;doxorubicin;methotrexate;vincristine
rs4793665	ABCC3	3	3.75	1	morphine
rs9895420	ABCC3	3	2.75	1	methotrexate
rs4148412	ABCC3		0.00	0
rs739923	ABCC3		0.00	0
rs733392	ABCC3		0.00	0
rs1978153	ABCC3		0.00	0
rs7216383	ABCC3		0.00	0
rs886493	ABCC3		0.00	0
rs28470592	ABCC3		0.00	0
rs4148415	ABCC3		0.00	0
rs11079921	ABCC3		0.00	0
rs8077268	ABCC3		0.00	0

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: transporter — ABCC subfamily

ChEMBL bioactivities

7 potent at pChembl≥5 of 50 total, top 7 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.20	IC50	631.5	nM	CYCLOSPORINE
5.96	IC50	1100	nM	CHEMBL589973
5.70	IC50	2000	nM	OLMESARTAN MEDOXOMIL
5.29	IC50	5100	nM	ETRAVIRINE
5.19	IC50	6390	nM	GLIMEPIRIDE
5.18	IC50	6650	nM	EPROSARTAN
5.03	IC50	9300	nM	MK-571

PubChem BioAssay actives

7 with measured affinity, of 716 total; 7 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
cyclosporine	1766762: Inhibition of benzmarone-stimulated MRP3 ATPase activity (unknown origin) in presence of GSH	ic50	0.6315	uM
2-[4-[4-(butylcarbamoyl)-2-[(2,4-dichlorophenyl)sulfonylamino]phenoxy]-3-methoxyphenyl]acetic acid	1473740: Inhibition of human MRP3 overexpressed in Sf9 insect cell membrane vesicles assessed as uptake of [3H]-estradiol-17beta-D-glucuronide in presence of ATP and GSH measured after 10 mins by membrane vesicle transport assay	ic50	1.1000	uM
Olmesartan Medoxomil	1473740: Inhibition of human MRP3 overexpressed in Sf9 insect cell membrane vesicles assessed as uptake of [3H]-estradiol-17beta-D-glucuronide in presence of ATP and GSH measured after 10 mins by membrane vesicle transport assay	ic50	2.0000	uM
Etravirine	586881: Inhibition of MRP3 expressed in MDCK2 cells assessed as cell growth inhibition by calcein and pheophorbide A efflux assays	ic50	5.1000	uM
4-ethyl-3-methyl-N-[2-[4-[(4-methylcyclohexyl)carbamoylsulfamoyl]phenyl]ethyl]-5-oxo-2H-pyrrole-1-carboxamide	1473740: Inhibition of human MRP3 overexpressed in Sf9 insect cell membrane vesicles assessed as uptake of [3H]-estradiol-17beta-D-glucuronide in presence of ATP and GSH measured after 10 mins by membrane vesicle transport assay	ic50	6.3900	uM
4-[[2-butyl-5-[(E)-2-carboxy-3-thiophen-2-ylprop-1-enyl]imidazol-1-yl]methyl]benzoic acid	1473740: Inhibition of human MRP3 overexpressed in Sf9 insect cell membrane vesicles assessed as uptake of [3H]-estradiol-17beta-D-glucuronide in presence of ATP and GSH measured after 10 mins by membrane vesicle transport assay	ic50	6.6500	uM
3-[[3-[(E)-2-(7-chloroquinolin-2-yl)ethenyl]phenyl]-[3-(dimethylamino)-3-oxopropyl]sulfanylmethyl]sulfanylpropanoic acid	1473740: Inhibition of human MRP3 overexpressed in Sf9 insect cell membrane vesicles assessed as uptake of [3H]-estradiol-17beta-D-glucuronide in presence of ATP and GSH measured after 10 mins by membrane vesicle transport assay	ic50	9.3000	uM

CTD chemical–gene interactions

213 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Cyclosporine	affects expression, affects cotreatment, decreases expression, affects export, decreases reaction (+1 more)	8
Rifampin	affects cotreatment, increases expression, decreases reaction, increases activity	7
Estradiol	affects cotreatment, increases expression, decreases expression, increases uptake	6
Benzo(a)pyrene	decreases methylation, increases expression, increases methylation	5
Tetrachlorodibenzodioxin	increases expression, affects cotreatment	5
Particulate Matter	increases abundance, increases expression, affects cotreatment	5
bisphenol A	affects expression, increases expression, affects cotreatment, decreases expression	4
sodium arsenite	affects expression, increases abundance, increases expression, decreases expression, affects cotreatment	4
estradiol-17 beta-glucuronide	increases reaction, increases uptake, affects transport, increases transport, decreases reaction (+1 more)	4
Acetaminophen	decreases activity, decreases expression, affects cotreatment	4
Bile Acids and Salts	increases transport, affects transport, decreases reaction, increases activity	4
Chenodeoxycholic Acid	increases expression, affects cotreatment, decreases expression	4
Cisplatin	increases expression, affects response to substance, decreases response to substance	4
Deoxycholic Acid	affects cotreatment, decreases expression, increases activity, increases expression	4
Doxorubicin	decreases response to substance, increases nitrosation, increases reaction	4
Indomethacin	decreases expression, affects export, decreases reaction, affects transport, increases expression (+1 more)	4
verlukast	decreases expression, decreases reaction, increases transport	3
calcein AM	increases reaction, decreases reaction, affects transport, increases transport	3
Resveratrol	increases reaction, increases transport, decreases expression, increases expression	3
Air Pollutants	affects cotreatment, increases abundance, increases expression, increases oxidation	3
Arsenic	affects cotreatment, affects expression, increases expression, increases abundance	3
Dexamethasone	increases activity, increases expression, affects cotreatment, decreases expression, affects transport (+1 more)	3
Lithocholic Acid	increases activity, increases expression	3
Methotrexate	affects response to substance, affects expression	3
Valproic Acid	affects expression, decreases expression, decreases methylation, increases expression	3
nickel sulfate	increases expression	2
methacrylaldehyde	affects cotreatment, increases expression, increases oxidation, increases abundance	2
diallyl trisulfide	decreases expression, increases expression	2
perfluorooctane sulfonic acid	decreases expression, increases expression	2
TAK-875	decreases activity, decreases reaction, increases transport	2

ChEMBL screening assays

37 unique, capped per target: 21 binding, 16 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1692699	Binding	Inhibition of MRP3 expressed in MDCK2 cells assessed as cell growth inhibition by calcein and pheophorbide A efflux assays	Interaction potential of etravirine with drug transporters assessed in vitro. — Antimicrob Agents Chemother
CHEMBL1743161	ADMET	Substrates of transporters of clinical importance in the absorption and disposition of drugs, MPR3	Membrane transporters in drug development. — Nat Rev Drug Discov

Cellosaurus cell lines

4 cell lines: 4 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B1IL	Abcam HeLa ABCC3 KO	Cancer cell line	Female
CVCL_B6A2	C2BBe1 MRP3 KO	Cancer cell line	Male
CVCL_B6A4	C2BBe1 MRP3/MRP4 KO	Cancer cell line	Male
CVCL_B6AI	HepaRG MRP3 KO	Cancer cell line	Female

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.