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): 258 total — 4 pathogenic
• GTEx eGene: eQTL in 35 tissues, sQTL in 28 (q < 0.05)
• ChEMBL bioactivity: 43 clinical-phase molecules tested; no curated mechanism-of-action drug
• Precision-oncology evidence (CIViC): 1 curated variant–drug association
• Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 0.83 (unconstrained)
• 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: 67 — 45 protein_coding, 13 nonsense_mediated_decay, 5 retained_intron, 4 protein_coding_CDS_not_defined

MANE Select: ENST00000285238

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 3, TSL 2: 3, TSL 3: 5, TSL 4: 2, TSL 5: 4

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, ENST00000974704, ENST00000974705, ENST00001056376, ENST00001056378, ENST00001056379, ENST00001056380, ENST00001056381, ENST00001056382, ENST00001056383, ENST00001098673, ENST00001098674, ENST00001110470, ENST00001110471, ENST00001110472, ENST00001110473, ENST00001110474, ENST00001113376, ENST00001113377, ENST00001113378, ENST00001117516, ENST00001125712, ENST00001125713, ENST00001125714, ENST00001125715, ENST00001136305

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.

Highest expression (Bgee): pancreatic ductal cell, adrenal gland, adrenal gland cortex, mucosa of transverse colon, adrenal cortex.

Genetic regulation across tissues (GTEx eQTL / sQTL)

ABCC3 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 35 tissues and its splicing (sQTL) in 28 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 63 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Skin Sun Exposed Lower leg	sqtl	2.6e-168	-1.35	17:50679576:C:T
Esophagus Mucosa	sqtl	4.9e-112	-1.30	17:50679576:C:T
Skin Not Sun Exposed Suprapubic	sqtl	1.3e-111	-1.25	17:50679576:C:T
Cells Cultured fibroblasts	sqtl	2.7e-92	-1.20	17:50679576:C:T
Lung	sqtl	4.4e-92	-1.19	17:50679576:C:T
Thyroid	sqtl	5.3e-76	-1.18	17:50679576:C:T
Pancreas	sqtl	1.1e-72	-1.22	17:50679576:C:T
Artery Aorta	sqtl	2.8e-67	-1.22	17:50679576:C:T
Adrenal Gland	sqtl	2.1e-62	+1.12	17:50679576:C:T
Liver	sqtl	5.6e-61	-1.22	17:50679576:C:T
Nerve Tibial	eqtl	2.9e-49	-0.56	17:50634726:C:T
Artery Tibial	eqtl	7.8e-46	-0.44	17:50635819:A:G
Whole Blood	eqtl	1.3e-45	-0.38	17:50679576:C:T
Stomach	sqtl	2.8e-33	-1.12	17:50679576:C:T
Cells Cultured fibroblasts	eqtl	8.4e-31	-0.24	17:50634726:C:T
Lung	eqtl	1.3e-27	-0.42	17:50634726:C:T
Esophagus Muscularis	eqtl	2.6e-27	-0.38	17:50634726:C:T
Adipose Subcutaneous	sqtl	9.4e-26	-0.72	17:50679576:C:T
Heart Atrial Appendage	eqtl	4.9e-25	-0.39	17:50634726:C:T
Artery Tibial	sqtl	7.4e-25	-0.77	17:50679576:C:T

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

showing 100 of 290 tissues 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
islet of Langerhans	UBERON:0000006	91.99	gold quality
metanephros cortex	UBERON:0010533	91.75	gold quality
stromal cell of endometrium	CL:0002255	91.49	gold quality
monocyte	CL:0000576	91.36	gold quality
esophagus mucosa	UBERON:0002469	91.14	gold quality
endometrium epithelium	UBERON:0004811	91.13	gold quality
small intestine	UBERON:0002108	91.08	gold quality
jejunal mucosa	UBERON:0000399	90.80	gold quality
mononuclear cell	CL:0000842	90.73	gold quality
sperm	CL:0000019	90.34	silver quality
leukocyte	CL:0000738	90.30	gold quality
minor salivary gland	UBERON:0001830	90.30	gold quality
skin of leg	UBERON:0001511	89.94	gold quality
right lobe of thyroid gland	UBERON:0001119	89.84	gold quality
fundus of stomach	UBERON:0001160	89.84	gold quality
skin of abdomen	UBERON:0001416	89.51	gold quality
visceral pleura	UBERON:0002401	89.41	gold quality
granulocyte	CL:0000094	89.28	gold quality
upper lobe of left lung	UBERON:0008952	89.10	gold quality
left lobe of thyroid gland	UBERON:0001120	88.78	gold quality
seminal vesicle	UBERON:0000998	88.61	gold quality
vermiform appendix	UBERON:0001154	88.34	gold quality
upper lobe of lung	UBERON:0008948	88.10	gold quality
mouth mucosa	UBERON:0003729	87.65	gold quality
zone of skin	UBERON:0000014	87.59	gold quality
intestine	UBERON:0000160	87.40	gold quality
male germ cell	CL:0000015	87.37	silver quality
caecum	UBERON:0001153	87.11	gold quality
corpus epididymis	UBERON:0004359	86.81	gold quality
urinary bladder	UBERON:0001255	86.62	gold quality
large intestine	UBERON:0000059	86.41	gold quality
right lung	UBERON:0002167	86.29	gold quality
saliva-secreting gland	UBERON:0001044	86.15	gold quality
colon	UBERON:0001155	86.14	gold quality
thyroid gland	UBERON:0002046	85.90	gold quality
spleen	UBERON:0002106	85.88	gold quality
right coronary artery	UBERON:0001625	85.71	gold quality
prostate gland	UBERON:0002367	85.41	gold quality
lymph node	UBERON:0000029	85.37	gold quality
mucosa of urinary bladder	UBERON:0001259	84.75	gold quality
aorta	UBERON:0000947	84.61	gold quality
left coronary artery	UBERON:0001626	84.49	gold quality
endocervix	UBERON:0000458	84.27	gold quality
caput epididymis	UBERON:0004358	84.00	gold quality
epithelial cell of pancreas	CL:0000083	83.68	gold quality
coronary artery	UBERON:0001621	83.65	gold quality
vagina	UBERON:0000996	83.45	gold quality
lung	UBERON:0002048	82.98	gold quality
adult mammalian kidney	UBERON:0000082	82.90	gold quality
decidua	UBERON:0002450	82.72	silver quality
tonsil	UBERON:0002372	82.59	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	82.18	gold quality
jejunum	UBERON:0002115	82.04	gold quality
nephron tubule	UBERON:0001231	82.00	gold quality
nipple	UBERON:0002030	81.72	gold quality
cardia of stomach	UBERON:0001162	81.71	gold quality
esophagus	UBERON:0001043	80.96	gold quality
ectocervix	UBERON:0012249	80.82	gold quality
secondary oocyte	CL:0000655	80.81	gold quality
cortex of kidney	UBERON:0001225	80.79	gold quality
layer of synovial tissue	UBERON:0007616	80.72	gold quality
kidney	UBERON:0002113	80.68	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	79.81	silver quality
diaphragm	UBERON:0001103	79.50	gold quality
esophagus squamous epithelium	UBERON:0006920	79.28	gold quality
cartilage tissue	UBERON:0002418	79.22	silver quality
subcutaneous adipose tissue	UBERON:0002190	79.20	gold quality
tibial artery	UBERON:0007610	78.95	gold quality
popliteal artery	UBERON:0002250	78.93	gold quality
oocyte	CL:0000023	78.91	silver 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

HPA expression

RNA tissue specificity: Tissue enhanced

showing 60 of 78 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Liver	tissue	20.5	not detected
Adrenal gland	tissue	15.1	high
Stomach 1	tissue	14.1	medium
Colon	tissue	13.6	high
Duodenum	tissue	11.3	medium
Gallbladder	tissue	11.2	high
Rectum	tissue	8.2	high
Pancreas	tissue	6.5	medium
Small intestine	tissue	6.2	medium
Skin 1	tissue	5.3	medium
Seminal vesicle	tissue	5.2	high
Urinary bladder	tissue	4.7	medium
Periaqueductal gray	tissue	4.1
Hypothalamus	tissue	3.8
Vagina	tissue	3.5	not detected
Appendix	tissue	3.2	high
Salivary gland	tissue	3.1	low
Substantia nigra	tissue	3.0
Lung	tissue	3.0	low
Pons	tissue	2.9
Spinal cord	tissue	2.9
Septum	tissue	2.8
Choroid plexus	tissue	2.7
Medulla oblongata	tissue	2.5
Esophagus	tissue	2.3	low
Midbrain	tissue	2.3
Corpus callosum	tissue	2.3
Amygdala	tissue	2.2
Thalamus	tissue	2.2
Spleen	tissue	2.2	not detected
Ventral forebrain	tissue	2.2
Basal ganglia	tissue	2.0	not detected
Putamen	tissue	2.0
Superior colliculi	tissue	1.9
Lymph node	tissue	1.8	not detected
Kidney	tissue	1.8	medium
Hippocampal formation	tissue	1.8
Epididymis	tissue	1.7	not detected
Locus coeruleus	tissue	1.7
Hippocampus	tissue	1.6	not detected
Tonsil	tissue	1.6	not detected
Cervix	tissue	1.4	low
Cerebral cortex	tissue	1.3	not detected
Nucleus accumbens	tissue	1.3
Insular cortex	tissue	1.3
Prefrontal cortex	tissue	1.2
Smooth muscle	tissue	1.2	low
Motor cortex	tissue	1.2
Entorhinal cortex	tissue	1.2
Retrosplenial cortex	tissue	1.2
Temporal cortex	tissue	1.2
Breast	tissue	1.1	low
Postcentral gyrus	tissue	1.1
Retrosplenial and cingulate cortex	tissue	1.1
Adipose tissue	tissue	1.0	not detected
Frontal cortex	tissue	1.0
Placenta	tissue	1.0	low
Thyroid gland	tissue	1.0	low
Olfactory bulb	tissue	1.0
Caudate putamen	tissue	1.0

Brain sub-regions (HPA Brain Atlas): detected in 191; highest nTPM — Area postrema (14.4), Nucleus raphe pallidus (9.7), Blood vessel (8.3), Medial olivary nucleus (8.2), Nucleus raphe obscurus (7.8).

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

Functional genomics

gnomAD constraint: pLI 2.71e-28, LOEUF 0.831, missense Z 1.25 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000285238 — one region, missense o/e 0.95.

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)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:1923658) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 5 distinct phenotype terms.

Mouse phenotype (MP)	Records
decreased chemically-elicited antinociception	1
abnormal bile salt level	1
increased circulating bilirubin level	1
abnormal bile salt homeostasis	1
abnormal xenobiotic pharmacokinetics	1

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Oryza sativa Indica Group	A2XCD4	100.0%	Diamond
Saccharomyces cerevisiae EC1118	C8ZCR2	100.0%	Diamond
Saccharomyces cerevisiae S288C	P0CE69	100.0%	Diamond
Saccharomyces cerevisiae	P0CE70	100.0%	Diamond
Oryza sativa Japonica Group	Q10RX7	100.0%	Diamond
Oryctolagus cuniculus	P82451	98.1%	Diamond
Cricetus cricetus	Q09427	98.0%	Diamond
Macaca fascicularis	Q864R9	97.6%	Diamond
Arabidopsis thaliana	Q7FB56	94.8%	Diamond
Canis lupus familiaris	Q6UR05	93.1%	Diamond
Bos taurus	Q8HXQ5	93.1%	Diamond
Zea mays	A7KVC2	90.5%	Diamond
Dictyostelium discoideum	Q8ST87	86.2%	Diamond
Gallus gallus	Q5F364	79.0%	Diamond
Danio rerio	F1RBC8	71.2%	Diamond
Schizosaccharomyces pombe 972h-	Q10185	63.4%	Diamond
Nakaseomyces glabratus CBS 138	Q6FWS5	55.3%	Diamond
Pyricularia oryzae 70-15	G4N2B5	47.9%	Diamond
Cryptococcus neoformans H99	J9VQH1	42.5%	Diamond
Mycosarcoma maydis	A0A0D1CZ63	41.8%	Diamond
Talaromyces islandicus	A0A0U1LQE1	41.3%	Diamond
Aspergillus versicolor	P9WEL8	41.0%	Diamond
Candida albicans SC5314	Q5A762	41.0%	Diamond
Aspergillus nidulans FGSC A4	A0A1U8QTJ9	40.6%	Diamond
Leishmania tarentolae	P21441	40.3%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
CACNA1G-AS1	ncRNA	253962
SPATA20	protein-coding	64847
CACNA1G	protein-coding	8913
ANKRD40	protein-coding	91369
LUC7L3	protein-coding	51747
EPN3	protein-coding	55040
MIR8059	ncRNA	102466918
ANKRD40CL	protein-coding	55018

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): D6RAB7, D6RJE5, O15438, 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)

• 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)
• testosterone 17-sulfate(in) + ATP + H2O = testosterone 17-sulfate(out) + ADP + phosphate + H(+) (RHEA:86827)
• androsterone 3alpha-sulfate(in) + ATP + H2O = androsterone 3alpha-sulfate(out) + ADP + phosphate + H(+) (RHEA:86831)

UniProt features (224 total): helix 86, strand 34, turn 30, 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 by resolution:

PDB	Title	Method	Resolution (Å)
8HVH	Cryo-EM structure of ABC transporter ABCC3	ELECTRON MICROSCOPY	3.07
8IZP	Multidrug resistance-associated protein 3	ELECTRON MICROSCOPY	3.31
8HW4	Cryo-EM structure of dehydroepiandrosterone sulfate-bound human ABC transporter ABCC3 in …	ELECTRON MICROSCOPY	3.52
8HW2	Cryo-EM structure of beta-estradiol 17-(beta-D-glucuronide)-bound human ABC transporter …	ELECTRON MICROSCOPY	3.65

Predicted structure (AlphaFold)

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

Human Protein Atlas

Protein class: Enzymes, ENZYME proteins, Metabolic proteins, Transporters, Primary Active Transporters, Predicted membrane proteins, Predicted intracellular proteins, Cancer-related genes, Candidate cancer biomarkers

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): plasma membrane; basal body

Antibody reliability (HPA): IH enhanced · IF supported

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)

Position	Role
661–668	ATP
1323–1330	ATP

Post-translational modifications (2)

Type	Positions
Phosphoserine	908, 911

Glycosylation sites (3)

Type	Positions
N-linked (glcnac…) asparagine	18, 1006, 1007

Function

Pathways and Gene Ontology

Reactome pathways

5 curated (TAS) of 16; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

16 pathways:

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

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 (10): 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)

GO Molecular Function (12): 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), icosanoid transmembrane transporter activity (GO:0071714), ABC-type transporter activity (GO:0140359), nucleotide binding (GO:0000166), transmembrane transporter activity (GO:0022857)

GO Cellular Component (4): plasma membrane (GO:0005886), basal plasma membrane (GO:0009925), basolateral plasma membrane (GO:0016323), membrane (GO:0016020)

Reactome top-level categories

11 top-level categories:

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

41 GO namespaces:

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
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
anion 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
basal plasma membrane	1
cellular anatomical structure	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 12 of 26 annotations. The rest are phylogenetic / computational / electronic (IEA).

12 experimentally-supported GO terms:

GO term	NS	Evidence
leukotriene transport	BP	mutant phenotype
xenobiotic transmembrane transport	BP	mutant phenotype
xenobiotic transport	BP	direct assay
basal plasma membrane	CC	direct assay
basolateral plasma membrane	CC	direct assay
plasma membrane	CC	direct assay
ABC-type glutathione S-conjugate transporter activity	MF	direct assay
ABC-type xenobiotic transporter activity	MF	direct assay
ATPase-coupled transmembrane transporter activity	MF	direct assay
glucuronoside transmembrane transporter activity	MF	direct assay
icosanoid transmembrane transporter activity	MF	direct assay
xenobiotic transmembrane transporter activity	MF	direct assay

Protein interactions and networks

STRING

showing 15 of 1,152 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ABCC3	SLC51A	Q86UW1	904
ABCC3	SLC51B	Q86UW2	803
ABCC3	CYP7A1	P22680	766
ABCC3	SLCO1B1	Q9Y6L6	741
ABCC3	SLC10A1	Q14973	719
ABCC3	MRPS7	Q9Y2R9	719
ABCC3	SLCO1B3	Q9NPD5	719
ABCC3	SLCO1A2	P46721	716
ABCC3	SLCO2B1	O94956	702
ABCC3	SLC22A7	Q9Y694	684
ABCC3	FGF19	O95750	634
ABCC3	NR1H4	Q96RI1	602
ABCC3	UGT1A6	P19224	599
ABCC3	SLC22A1	O15245	595
ABCC3	SLC10A2	Q12908	593

IntAct

Human interaction partners of ABCC3 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

1 partners by confidence:

Partner	Interaction type	MIscore	Records
MLH1	physical association	0.370	1

BioGRID (36 interactions; top human partners by supporting records): ATP9A (Co-fractionation), CANX (Co-fractionation), CRELD1 (Affinity Capture-MS), CUL3 (Affinity Capture-MS), EEF2 (Co-fractionation), EGFR (Affinity Capture-MS), ESR2 (Affinity Capture-MS), FLOT2 (Proximity Label-MS), HIST1H1E (Cross-Linking-MS (XL-MS)), HNRNPH1 (Affinity Capture-RNA), HRAS (Proximity Label-MS), IDH3A (Co-fractionation), MIR150 (Protein-RNA), MLH1 (Two-hybrid), MTDH (Protein-RNA)

SIGNOR signaling

1 signaling interactions:

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

Disease & clinical

Genetic variants

Variant evidence for ABCC3: 258 ClinVar records (4 pathogenic / likely pathogenic); 1 CIViC cancer variant; 4 PharmGKB clinical annotations. Per-variant detail is on Sugi Variant.

ClinVar

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

Classification	Count (floor)
Pathogenic	4
Likely pathogenic	0
Uncertain significance	179
Likely benign	29
Benign	5

Top pathogenic / likely-pathogenic (4)

Showing all 4 pathogenic / likely-pathogenic ClinVar records, ranked by ClinVar review status (expert panel → multiple submitters → single submitter), then by number of submitting labs.

Variant ID	HGVS	Classification	Review	Submitters
59589	GRCh38/hg38 17q21.32-22(chr17:49137864-52147810)x1	Pathogenic	criteria provided, single submitter	1
59590	GRCh38/hg38 17q21.33-22(chr17:49974533-56807609)x1	Pathogenic	criteria provided, single submitter	1
2692407	Single allele	Pathogenic	criteria provided, single submitter	1
3242218	Single allele	Pathogenic	no assertion criteria provided	1

Per-variant reference — Sugi Variant

Explore ABCC3’s pathogenic and likely-pathogenic variants individually — each with its ClinVar classification and conditions, applied ACMG criteria (ClinGen expert panel, where curated), the calibrated in-silico predictors (AlphaMissense, REVEL, SaProt, conservation), gnomAD frequency, and the predictor-disagreement QC signal — on Sugi Variant.

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 37 predictions of 2,965):

Position(s)	Effect	Δscore	Sites
17:50655830–50655831	acceptor_loss	1.0000	5
17:50657184–50657185	donor_loss	1.0000	5
17:50659369–50659370	donor_loss	1.0000	5
17:50660915–50660916	acceptor_gain	1.0000	2
17:50663856	donor_gain	1.0000
17:50665139	acceptor_gain	1.0000
17:50667551	acceptor_gain	1.0000
17:50667552–50667553	acceptor_loss	1.0000	5
17:50667758–50667759	donor_loss	1.0000	6
17:50667861–50667862	acceptor_loss	1.0000	6

AlphaMissense

2,286 missense substitutions predicted likely pathogenic (of 9,915 scored), across 744 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
D1450	8	0.987	0.996
D782	8	0.983	0.993
H1482	8	0.983	0.997
D775	8	0.977	0.991
D776	8	0.963	0.990
D416	8	0.960	0.981
D1457	8	0.955	0.981
N708	8	0.939	0.984
D732	8	0.934	0.959
F569	8	0.929	0.989
F1517	8	0.928	0.981
D1461	8	0.907	0.974
F711	8	0.899	0.973
F1337	8	0.895	0.969
F634	8	0.888	0.980
F1472	8	0.885	0.983
S1427	8	0.863	0.985
F1151	8	0.833	0.971
D1385	8	0.780	0.893
E1451	7	0.997	0.998

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

2 prognostic cancer types:

Cancer	Prognostic	p-value
Liver Hepatocellular Carcinoma (TCGA)	unfavorable	0.000243
Kidney Renal Clear Cell Carcinoma (TCGA)	favorable	0.000636

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)

MeSH disease descriptors

1 disease descriptors:

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

Phase ≥1, by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 887,788 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

43 molecules by phase:

Molecule	Name	Phase	Patents
CHEMBL495	ALPROSTADIL	4	13,615
CHEMBL393220	ATORVASTATIN CALCIUM	4	80,610
CHEMBL957	BOSENTAN	4	16,616
CHEMBL1370	BUDESONIDE	4	73,656
CHEMBL474579	CEFOTETAN	4	15,796
CHEMBL1292	CLOFAZIMINE	4	15,677
CHEMBL160	CYCLOSPORINE	4	169,776
CHEMBL953	ENTACAPONE	4	16,953
CHEMBL56337	EPALRESTAT	4	111
CHEMBL813	EPROSARTAN	4	19,625
CHEMBL456	ETHACRYNIC ACID	4	20,123
CHEMBL3140361	ETHAMBUTOL HYDROCHLORIDE	4	109
CHEMBL308954	ETRAVIRINE	4	11,476
CHEMBL1908360	EVEROLIMUS	4	74,649
CHEMBL2220442	FLUVASTATIN	4	54,000
CHEMBL1481	GLIMEPIRIDE	4	33,554
CHEMBL472	GLYBURIDE	4	53,640
CHEMBL6	INDOMETHACIN	4	157,305
CHEMBL1513	IRBESARTAN	4	31,879
CHEMBL729	LOPINAVIR	4	28,618
CHEMBL1200865	LOTEPREDNOL ETABONATE	4
CHEMBL1200692	OLMESARTAN MEDOXOMIL	4
CHEMBL2103772	RACECADOTRIL	4
CHEMBL1272	REPAGLINIDE	4
CHEMBL374478	RIFAMPIN	4
CHEMBL1660	RIFAPENTINE	4
CHEMBL1617	RIFAXIMIN	4
CHEMBL163	RITONAVIR	4
CHEMBL1744447	ROSUVASTATIN CALCIUM	4
CHEMBL114	SAQUINAVIR	4
CHEMBL282724	SITAXENTAN	4
CHEMBL421	SULFASALAZINE	4
CHEMBL1017	TELMISARTAN	4
CHEMBL1201182	TEMSIROLIMUS	4
CHEMBL452231	TENIPOSIDE	4
CHEMBL1324	TOLCAPONE	4
CHEMBL408	TROGLITAZONE	4
CHEMBL1096885	VALRUBICIN	4
CHEMBL5087506	ADMILPARANT	3
CHEMBL5483011	INDINAVIR	3
CHEMBL77305	RUBITECAN	3
CHEMBL4297270	BMS-986020	2
CHEMBL383634	GLIQUIDONE	2

Clinical evidence (CIViC)

Drug × variant × indication, from 1 curated evidence items. CIViC evidence level: A (validated) → B (clinical) → C (case study) → D (preclinical) → E (inferential).

1 predictive associations by evidence level:

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

CIViC curated variants (1)

Named clinical variants curated in CIViC for this gene (the catalogue beneath the predictive evidence above):

Amplification (transcript amplification).

PharmGKB: 1 entry (CPIC guideline: no)

PharmGKB clinical annotations

4 annotations by evidence level (1 strongest → 4):

Variant	Association	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

4 variants:

Variant	Genes	Level	Score	#Clin annots	Drugs
rs1051640	ABCC3	3	2.00	1	cisplatin
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

PharmGKB variant annotations

Per-publication pharmacogenomic findings for this gene (significant associations).

23 published findings:

Variant	Drug(s)	Category	Finding	PMID
rs1051640	cisplatin	Toxicity	Allele G is associated with increased risk of Ototoxicity when treated with cisplatin in children with Neoplasms as compared to allele A.	PMID:23588304
rs1051640	cisplatin	Toxicity	Allele G is associated with increased risk of Ototoxicity when treated with cisplatin in children with Neoplasms as compared to allele A.	PMID:25141953
rs4793665	morphine	Metabolism/PK	Genotype CC is associated with increased metabolism of morphine in children as compared to genotypes CT + TT.	PMID:25155932
rs4793665	methotrexate	Metabolism/PK	Allele C is associated with decreased concentrations of methotrexate in children with Osteosarcoma as compared to allele T.	PMID:27566582
rs4148412	morphine	Toxicity	Allele T is associated with increased severity of Hypoventilation when treated with morphine in children with Sleep Apnea Syndromes and Tonsillectomy as compared to allele C.	PMID:26810133
rs739923	morphine	Toxicity	Allele G is associated with increased severity of Hypoventilation when treated with morphine in children with Sleep Apnea Syndromes and Tonsillectomy as compared to allele A.	PMID:26810133
rs733392	morphine	Toxicity	Allele G is associated with increased severity of Hypoventilation when treated with morphine in children with Sleep Apnea Syndromes and Tonsillectomy as compared to allele A.	PMID:26810133
rs1978153	morphine	Toxicity	Allele C is associated with increased severity of Hypoventilation when treated with morphine in children with Sleep Apnea Syndromes and Tonsillectomy as compared to allele G.	PMID:26810133
rs7216383	morphine	Toxicity	Allele T is associated with increased severity of Hypoventilation when treated with morphine in children with Sleep Apnea Syndromes and Tonsillectomy as compared to allele C.	PMID:26810133
rs886493	morphine	Toxicity	Allele G is associated with increased severity of Hypoventilation when treated with morphine in children with Sleep Apnea Syndromes and Tonsillectomy as compared to allele T.	PMID:26810133
rs4148412	morphine-3-glucuronide	Metabolism/PK	Genotype TT is associated with increased concentrations of morphine-3-glucuronide in children with tonsillectomy as compared to genotypes CC + CT.	PMID:26810133
rs4793665	morphine-3-glucuronide, morphine-6-glucuronide	Metabolism/PK	Genotype CC is associated with increased concentrations of morphine-3-glucuronide and morphine-6-glucuronide in children with Scoliosis or tonsillectomy as compared to genotypes CT + TT.	PMID:26810133
rs4793665	morphine	Metabolism/PK	Allele T is associated with decreased clearance of morphine in children as compared to allele C.	PMID:32090339
rs4148416	methotrexate	Metabolism/PK	Genotype TT is associated with increased clearance of methotrexate in children with Precursor Cell Lymphoblastic Leukemia-Lymphoma as compared to genotypes CC + CT.	PMID:35446233
rs11079921	fentanyl	Metabolism/PK	Allele C is associated with increased clearance of fentanyl in children with Pain and Premature Birth as compared to allele T.	PMID:39025933
rs8077268	fentanyl	Metabolism/PK	Allele T is associated with increased clearance of fentanyl in children with Pain and Premature Birth as compared to allele C.	PMID:39025933
rs9895420	pitavastatin	Metabolism/PK	Genotype AA is associated with decreased concentrations of pitavastatin in healthy individuals as compared to genotypes AT + TT.	PMID:42212460
rs2277624	methotrexate	Efficacy	Genotype CT is associated with decreased clinical benefit to methotrexate in people with Rheumatoid arthritis as compared to genotype CC.	PMID:42265358
rs9895420	methotrexate	Efficacy	Genotypes AA + AT are associated with decreased event free survival when treated with methotrexate in people with Precursor Cell Lymphoblastic Leukemia-Lymphoma as compared to genotype TT.	PMID:21606946
rs9895420	methotrexate	Toxicity, Metabolism/PK	Genotypes AA + AT are associated with increased plasma levels of methotrexate in people with Precursor Cell Lymphoblastic Leukemia-Lymphoma as compared to genotype TT.	PMID:21606946
rs9895420	methotrexate	Efficacy	Genotypes AA + AT are associated with increased risk of relapse in the central nervous system when treated with methotrexate in people with Precursor Cell Lymphoblastic Leukemia-Lymphoma as compared to genotype TT.	PMID:21606946
rs4148405	busulfan, cytarabine, etoposide	Efficacy, Toxicity	Allele G is associated with decreased Disease-Free Survival when treated with busulfan, cytarabine and etoposide in people with Leukemia, Myeloid, Acute as compared to allele T.	PMID:23677058
rs4148416	cisplatin, cyclophosphamide, doxorubicin, methotrexate, vincristine	Efficacy	Allele T is associated with increased risk of death when treated with cisplatin, cyclophosphamide, doxorubicin, methotrexate and vincristine in people with Osteosarcoma as compared to allele C.	PMID:22016816

GtoPdb / IUPHAR curated pharmacology

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

Target class: transporter — ABCC subfamily

Binding affinities (BindingDB)

133 measured of 571 human assays (620 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
1-(2-{4-[5-chloro-1-(4-fluorophenyl)-1H-indol-3-yl]piperidin-1-yl}ethyl)imidazolidin-2-one	KI	0.38 nM
2,2-dimethylbutyric acid, 8-ester with (4R,6R)-6-(2-((1S,2S,6R,8S,8aR)-1,2,6,7,8,8a-hexahydro-8-hydroxy-2,6-dimethyl-1-naphthyl)ethyl)tetrahydro-4-hydroxy-2H-pyran-2-one	IC50	0.9 nM
escitalopram	KI	1 nM
cid_1548953	KI	1 nM
(1R)-N-(prop-2-yn-1-yl)-2,3-dihydro-1H-inden-1-amine	KI	1.4 nM
4-[2-(tert-butylamino)-1-hydroxyethyl]-2-(hydroxymethyl)phenol	EC50	1.5 nM
5-[2-(4-Benzo[d]isothiazol-3-yl-piperazin-1-yl)-ethyl]-6-chloro-1,3-dihydro-indol-2-one	KI	1.6 nM
CHEMBL195	KI	1.6 nM
(S)-4-((3-(2-(dimethylamino)ethyl)-1H-indol-5-yl)methyl)oxazolidin-2-one	KD	1.8 nM
Permax	KI	1.91 nM
2-methyl-2-[4-(3-methyl-2-oxo-8-quinolin-3-ylimidazo[4,5-c]quinolin-1-yl)phenyl]propanenitrile	IC50	2 nM	US-9284315: Three-ring PI3K and/or mTOR inhibitor
(R)-3-methyl-1-((S)-3-phenyl-2-(pyrazine-6-carboxamido)propanamido)butylboronic acid	IC50	2.4 nM
5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-(piperidin-1-yl)-1H-pyrazole-3-carboxamide	KD	2.5 nM
2-(3-CYANO-4-ISOBUTOXY-PHENYL)-4-METHYL-5-THIAZOLE-CARBOXYLIC ACID	IC50	2.9 nM
(1S,3R,5Z,7E)-9,10-secocholesta-5,7,10(19)-triene-1,3,25-triol	EC50	3 nM
(2-{4-[(1Z)-1,2-diphenylbut-1-en-1-yl]phenoxy}ethyl)dimethylamine	KI	5 nM
1-(4-Amino-6,7-dimethoxy-2-quinazolinyl)-4-((tetrahydro-2-furanyl)carbonyl)piperazine	IC50	5 nM
Staurosporine, 8	IC50	6.5 nM
FCE-21336	EC50	13 nM
Amisulpride	KI	13 nM
4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzene-1-sulfonamide	KI	16 nM
(+/-)-12-Methyl-1,2,3,4,9,13b-hexahydro-2,4a,5-triaza-tribenzo[a,c,e]cycloheptene	KI	18 nM
2-Methyl-butyric acid 8-[2-(4-hydroxy-6-oxo-tetrahydro-pyran-2-yl)-ethyl]-7-methyl-1,2,3,7,8,8a-hexahydro-naphthalen-1-yl ester((+)-compactin)	IC50	23 nM
(3E)-3-(6H-benzo[c][1]benzoxepin-11-ylidene)-N,N-dimethylpropan-1-amine	KI	25 nM	US-8629135: Pharmaceutical compositions comprising RET inhibitors and methods for the treatment of cancer
(2-{4-[(2-butyl-1-benzofuran-3-yl)carbonyl]-2,6-diiodophenoxy}ethyl)diethylamine	KI	25 nM
CS-514	IC50	30 nM
1-(4-{3-[4-(6-Fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-propoxy}-3-methoxy-phenyl)-ethanone	KI	33 nM
(+/-)1-(4-tert-butylphenyl)-4-(4-(hydroxydiphenylmethyl)piperidin-1-yl)butan-1-ol	IC50	41 nM
1-(3-chlorophenyl)piperazine	KI	42 nM
5-Chloro-3-(4-methanesulfonyl-phenyl)-6’’-methyl-[2,3’’]bipyridinyl	IC50	70 nM
2-{3-[4-(3-chlorophenyl)piperazin-1-yl]propyl}-5-ethyl-4-(2-phenoxyethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one	KI	80 nM
[3-(2-Chloro-phenothiazin-10-yl)-propyl]-dimethyl-amine( Chlorpromazine)	KI	116 nM
APOKYN	KI	117 nM
N-hydroxy-N’-phenyloctanediamide	IC50	140 nM
8-Chloro-11-(4-methyl-piperazin-1-yl)-5H-dibenzo[b,e][1,4]diazepine(Clopazine)	IC50	150 nM
p-aminophenyl sulfone	KI	183 nM
4-[4-(4-Chloro-phenyl)-4-hydroxy-piperidin-1-yl]-1-(4-fluoro-phenyl)-butan-1-one;propionate(HCl)	KI	190 nM
Urapidil	KI	213 nM
Asendin	KI	221 nM
4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-methoxy-benzamide;hydrochloride	IC50	280 nM	US-11147820: Methods for treating GI tract disorders
NORTRIPTYLINE	KI	294 nM
N,N-dimethyl-2-[5-(1H-1,2,4-triazol-1-ylmethyl)-1H-indol-3-yl]ethanamine	IC50	316 nM
2-(tert-butylamino)-1-(3-chlorophenyl)propan-1-one	IC50	330 nM
4-chloro-N-(2-morpholin-4-ylethyl)benzamide	IC50	360 nM
1-Butyl-3-(p-methylphenylsulfonyl)urea	IC50	380 nM
NSC_4850	KI	447 nM
Amitriptylin	KI	450 nM
1-[4-[4-[[2-(2,4-dichlorophenyl)-2-(imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]piperazin-1-yl]ethanone	IC50	500 nM	US-8987315: Metalloenzyme inhibitor compounds
N-[4-(7-Chloro-5-hydroxy-2,3,4,5-tetrahydro-benzo[b]azepine-1-carbonyl)-3-methyl-phenyl]-2-methyl-benzamide	IC50	580 nM
1,1’,1’’,1’’’-[disulfanediylbis(carbonothioylnitrilo)]tetraethane	IC50	590 nM

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 717 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

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

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

Via MONDO — disease-level, not drug-specific.

Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for ABCC3 across ~30M SureChEMBL compounds — explore on Sugi Predict.