ABCC1

Summary

ABCC1 (ATP binding cassette subfamily C member 1 (ABCC1 blood group), HGNC:51) is a protein-coding gene on chromosome 16p13.11, encoding Multidrug resistance-associated protein 1 (P33527). Mediates export of organic anions and drugs from the cytoplasm.

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 full transporter is a member of the MRP subfamily which is involved in multi-drug resistance. This protein functions as a multispecific organic anion transporter, with oxidized glutatione, cysteinyl leukotrienes, and activated aflatoxin B1 as substrates. This protein also transports glucuronides and sulfate conjugates of steroid hormones and bile salts. Alternatively spliced variants of this gene have been described but their full-length nature is unknown.

Source: NCBI Gene 4363 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hearing loss, autosomal dominant 77 (Moderate, GenCC) — +1 more curated relationship
• GWAS associations: 22
• Clinical variants (ClinVar): 564 total — 116 pathogenic, 41 likely-pathogenic
• Phenotypes (HPO): 5
• Druggable target: yes — 23 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_004996

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:51
Approved symbol	ABCC1
Name	ATP binding cassette subfamily C member 1 (ABCC1 blood group)
Location	16p13.11
Locus type	gene with protein product
Status	Approved
Aliases	GS-X
Ensembl gene	ENSG00000103222
Ensembl biotype	protein_coding
OMIM	158343
Entrez	4363

Gene structure

Transcript identifiers

Ensembl transcripts: 38 — 31 protein_coding, 3 retained_intron, 3 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000399408, ENST00000399410, ENST00000572882, ENST00000574224, ENST00000574761, ENST00000575422, ENST00000576557, ENST00000676806, ENST00000677164, ENST00000678422, ENST00000679043, ENST00000903504, ENST00000914138, ENST00000914139, ENST00000914140, ENST00000914141, ENST00000914142, ENST00000914143, ENST00000914144, ENST00000914145, ENST00000914146, ENST00000914147, ENST00000914148, ENST00000914149, ENST00000914150, ENST00000914151, ENST00000914152, ENST00000914153, ENST00000914154, ENST00000914155, ENST00000914156, ENST00000914157, ENST00000958971, ENST00000958972, ENST00000958973, ENST00000958974, ENST00000958975, ENST00000958977

RefSeq mRNA: 2 — MANE Select: NM_004996 NM_004996, NM_019862

CCDS: CCDS42122, CCDS45427

Canonical transcript exons

ENST00000399410 — 31 exons

Exon	Start	End
ENSE00000829969	16068156	16068302
ENSE00000829982	16071642	16071729
ENSE00000829986	16076326	16076401
ENSE00000830049	16121975	16122174
ENSE00000830060	16124789	16124915
ENSE00000830062	16125810	16125911
ENSE00000830069	16131789	16131935
ENSE00000830083	16134350	16134508
ENSE00000830086	16136478	16136644
ENSE00000830093	16138364	16138558
ENSE00001204619	16056092	16056295
ENSE00001836750	16141173	16143053
ENSE00003461200	16079352	16079478
ENSE00003472302	16106738	16106873
ENSE00003533611	16102627	16102717
ENSE00003577696	16083366	16083542
ENSE00003626408	16086824	16086991
ENSE00003634034	16036472	16036603
ENSE00003637114	16052724	16052816
ENSE00003637754	16048142	16048303
ENSE00003652402	16033109	16033170
ENSE00003652954	16016496	16016621
ENSE00003658884	16114766	16115076
ENSE00003659139	16045836	16046013
ENSE00003688001	16090405	16090588
ENSE00003691854	16111375	16111582
ENSE00003722622	16007816	16007992
ENSE00003729185	16009776	16009901
ENSE00003737912	16044450	16044680
ENSE00003740408	16014491	16014628
ENSE00003749002	15949616	15949799

Expression profiles

Bgee: expression breadth ubiquitous, 134 present calls, max score 95.56.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 23.2593 / max 545.4387, expressed in 1812 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
152947	20.7420	1807
152946	1.5019	1114
152963	0.5299	251
152957	0.4620	171
152954	0.0237	13

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
lower esophagus mucosa	UBERON:0035834	95.56	gold quality
lower esophagus	UBERON:0013473	95.09	gold quality
lower esophagus muscularis layer	UBERON:0035833	95.08	gold quality
stromal cell of endometrium	CL:0002255	94.96	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	93.68	gold quality
esophagus	UBERON:0001043	93.31	gold quality
ascending aorta	UBERON:0001496	93.27	gold quality
thoracic aorta	UBERON:0001515	93.25	gold quality
mucosa of stomach	UBERON:0001199	93.16	gold quality
left lobe of thyroid gland	UBERON:0001120	93.15	gold quality
right lobe of thyroid gland	UBERON:0001119	92.91	gold quality
descending thoracic aorta	UBERON:0002345	92.86	gold quality
thyroid gland	UBERON:0002046	92.66	gold quality
esophagus mucosa	UBERON:0002469	91.85	gold quality
adrenal tissue	UBERON:0018303	91.46	gold quality
prostate gland	UBERON:0002367	91.04	gold quality
bone marrow cell	CL:0002092	90.97	gold quality
skeletal muscle tissue	UBERON:0001134	90.82	gold quality
spleen	UBERON:0002106	90.33	gold quality
body of stomach	UBERON:0001161	89.86	gold quality
upper lobe of left lung	UBERON:0008952	89.73	gold quality
muscle layer of sigmoid colon	UBERON:0035805	89.71	gold quality
muscle tissue	UBERON:0002385	89.53	gold quality
fundus of stomach	UBERON:0001160	89.30	gold quality
urinary bladder	UBERON:0001255	89.21	gold quality
stomach	UBERON:0000945	89.18	gold quality
gastrocnemius	UBERON:0001388	89.15	gold quality
lymph node	UBERON:0000029	89.05	gold quality
muscle of leg	UBERON:0001383	88.85	gold quality
lung	UBERON:0002048	88.65	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.49

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): APP, ATF3, CEBPA, ETS1, FOXC1, GABPA, JUN, MYCN, NFE2L2, PAX1, PPARA, PSEN1, RBPJ, RUNX3, SP1, SP3, TP53, YBX1

miRNA regulators (miRDB)

92 targeting ABCC1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-4673	100.00	66.64	1490
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-145-5P	99.92	71.13	1836
HSA-MIR-5195-3P	99.92	70.92	1877
HSA-MIR-6783-3P	99.89	67.92	2059
HSA-MIR-1343-3P	99.89	66.78	1815
HSA-MIR-6780A-5P	99.88	66.69	2776
HSA-MIR-659-3P	99.85	70.69	1620
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-3180-5P	99.82	69.12	2422
HSA-MIR-6756-5P	99.82	67.97	2466
HSA-MIR-4307	99.82	70.45	3374
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-6875-3P	99.82	70.26	2983
HSA-MIR-3133	99.81	70.92	3506
HSA-MIR-6739-5P	99.80	67.87	2806
HSA-MIR-2052	99.79	69.37	2031
HSA-MIR-1273H-5P	99.77	66.32	2471
HSA-MIR-6733-5P	99.74	67.94	2759
HSA-MIR-4306	99.72	70.50	3630
HSA-MIR-149-3P	99.72	68.22	3963
HSA-MIR-4677-5P	99.70	70.09	1940
HSA-MIR-30B-3P	99.70	65.76	2325
HSA-MIR-6779-5P	99.70	65.76	2363

Literature-anchored findings (GeneRIF, showing 40)

• sequence deletion in Pseudoxanthoma elasticum (PMID:11439001)
• Immunolabeling and dye efflux assays indicate that MRP activity and functional expression levels are elevated in monocyte-derived dendritic cells when compared to those present in parental monocytes. (PMID:11600213)
• polyclonal antibodies recognizing both human and rodent MRP1 (PMID:11689020)
• MDR transpiorter proteins have a limited role in the treatment failure of patients treated with ifarubicin-based regimens (PMID:11755464)
• overexpression of MRP1 in DS brain may have some relevance to the disorder either by deranging substrate homeostasis or limiting drug access. (PMID:11771758)
• In vivo analysis of human multidrug resistance protein 1 (MRP1) activity using transient expression of fluorescently tagged MRP1. (PMID:11809686)
• Expression of MRP1 can be induced by nonsteroidal anti-inflammatory drugs in a reactive oxygen species-dependent but cyclooxygenase-2-independent manner. (PMID:11820781)
• determination of substrate specificity (PMID:11925441)
• MRP1 mRNA was detected in non-HTLV-1 Tax producing ATL cell lines, but MRP1 is not activated by transfected HTLV-1 Tax expression. (PMID:11937269)
• no difference of expression between diagnosis and relapse of AML; not associated with clinical resistant disease in AML (PMID:11986944)
• Antisense hairpin loop oligonucleotides as inhibitors of expression of multidrug resistance-associated protein 1: their stability in fetal calf serum and human plasma (PMID:11995968)
• Multidrug resistance-associated protein–reduction of expression in human leukaemia cells by antisense phosphorothioate olignucleotides (PMID:11996108)
• rate of uptake of arsenic trioxide and of antimony tartrate in GLC4 and GLC4/ADR cells overexpressing MRP1 (PMID:12018890)
• ATP hydrolysis causes a conformational change in MRP1 that reduces the affinity of the protein for this inhibitor (PMID:12034727)
• Mutations in mrp1 results in decreased organic anion transport and increased doxorubicin resistance in Hela cells (PMID:12042670)
• directly interacts with several tyrosine kinase inhibitors (PMID:12084474)
• cytoplasmic retraction of the amino terminus (PMID:12119019)
• S-decyl-glutathione nonspecifically stimulates the ATPase activity of the nucleotide-binding domains of the human multidrug resistance-associated protein, MRP1 (ABCC1). (PMID:12135486)
• evidence for the role of glycosylation in accessibility of the extracellular domains of human MRP1 (PMID:12146977)
• Results show efficient GTP hydrolysis by the N-terminal nucleotide binding domain (NBD1) of MRP1 (PMID:12163030)
• importance of Lys(332) and His(335) in determining substrate specificity and of Asp(336) in overall transport activity (PMID:12186871)
• the amino terminus of human MRP1 is important and that the Cys(7) residue plays a critical role in maintaining the proper structure and function of human MRP1 (PMID:12235150)
• Trp residues are critical for the transport activity and substrate specificity of MRP1 (PMID:12388549)
• MRP1 has a functional role in the maintenance of cellular folate homeostasis (PMID:12486126)
• RNA expression of this protein in breast cancer correlates with response to chemotherapy. (PMID:12576456)
• 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)
• MRP1 and MRP5 increase with trophoblast maturation, suggesting a particular role for these proteins in the organ functional developmen (PMID:12646196)
• MRP1 does not have a role in increased resistance to oxidative stress (PMID:12653207)
• ATP binding at nucleotide binding domain 1 at low concentration plays a more important regulatory role than the binding at high concentration and that ATP hydrolysis at nucleotide binding domain 2 plays a dominant role in LTC4 transport. (PMID:12783859)
• A novel silent mutation G816A in exon 8 was found (PMID:12856092)
• MRP1 and MRP2 were expressed in peripheral blood cells, with more than sevenfold higher MRP1 expression in all cell populations investigated. The MRP1 mRNA expression was highest in CD4+ cells >, followed by CD8+ > CD19+ > CD56+ cells. (PMID:12890151)
• Trp653 is involved in the binding of ATP to the nucleotide-binding domain 1 of multidrug-resistance-associated protein 1. (PMID:12954082)
• importance of polar and charged amino acid residues in transmembrane helix 14 of multidrug resistance protein 1 (MRP1/ABCC1) (PMID:12954620)
• structural data for MRP1 that might be used to elucidate its mechanism of transport (PMID:14561746)
• phospholipid translocation in the erythrocyte membrane depends on ATP and glutathione (PMID:14578045)
• Basal membrane localization of MRP1 in the placental trophoblast. (PMID:14580377)
• MRP1 transport function requres helices TM6, TM8, TM10, TM11, and TM14 and CL7 may play a differential role in coupling the activity of the nucleotide binding domains to the translocation of different substrates across the membrane (PMID:14722114)
• MRP1 may be a target for MYCN-mediated gene regulation (PMID:14737110)
• Refractory epilepsy phenotype in tuberous sclerosis can be associated with the expression of multidrug resistance MRP-1 transporter in epileptogenic cortical tubers. (PMID:14984901)
• both signature sequences of MRP1 are involved in ATP hydrolysis and must be intact for the ATP hydrolysis and the transport by MRP1. (PMID:15155846)

Cross-species orthologs

14 orthologs

Organism	Symbol	Gene ID
danio_rerio	abcc1	ENSDARG00000104719
mus_musculus	Abcc1	ENSMUSG00000023088
rattus_norvegicus	Abcc1	ENSRNOG00000022305
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	Mrp4	FBGN0263316
caenorhabditis_elegans		WBGENE00000477

Paralogs (11): CFTR (ENSG00000001626), ABCC8 (ENSG00000006071), ABCC2 (ENSG00000023839), ABCC9 (ENSG00000069431), ABCC6 (ENSG00000091262), ABCC3 (ENSG00000108846), ABCC5 (ENSG00000114770), ABCC11 (ENSG00000121270), ABCC10 (ENSG00000124574), ABCC4 (ENSG00000125257), ABCC12 (ENSG00000140798)

Protein

Protein identifiers

Multidrug resistance-associated protein 1 — P33527 (reviewed: P33527)

Alternative names: ATP-binding cassette sub-family C member 1, Glutathione-S-conjugate-translocating ATPase ABCC1, Leukotriene C(4) transporter

All UniProt accessions (5): P33527, A0A0A0MS99, A0A7I2V2E0, A0A7I2V4C6, I3L4X2

UniProt curated annotations — full annotation on UniProt →

Function. Mediates export of organic anions and drugs from the cytoplasm. Mediates ATP-dependent transport of glutathione and glutathione conjugates, leukotriene C4, estradiol-17-beta-o-glucuronide, methotrexate, antiviral drugs and other xenobiotics. Confers resistance to anticancer drugs by decreasing accumulation of drug in cells, and by mediating ATP- and GSH-dependent drug export. Hydrolyzes ATP with low efficiency. Catalyzes the export of sphingosine 1-phosphate from mast cells independently of their degranulation. Participates in inflammatory response by allowing export of leukotriene C4 from leukotriene C4-synthesizing cells. Mediates ATP-dependent, GSH-independent cyclic GMP-AMP (cGAMP) export. Thus, by limiting intracellular cGAMP concentrations negatively regulates the cGAS-STING pathway. Exports S-geranylgeranyl-glutathione (GGG) in lymphoid cells and stromal compartments of lymphoid organs. ABCC1 (via extracellular transport) with GGT5 (via GGG catabolism) establish GGG gradients within lymphoid tissues to position P2RY8-positive lymphocytes at germinal centers in lymphoid follicles and restrict their chemotactic transmigration from blood vessels to the bone marrow parenchyma. Mediates basolateral export of GSH-conjugated R- and S-prostaglandin A2 diastereomers in polarized epithelial cells.

Subunit / interactions. (Microbial infection) Interacts with human cytomegalovirus protein UL138; this interaction mediates MRP1 degradation via the lysosome.

Subcellular location. Cell membrane. Basolateral cell membrane.

Tissue specificity. Lung, testis and peripheral blood mononuclear cells.

Disease relevance. Deafness, autosomal dominant, 77 (DFNA77) [MIM:618915] A form of non-syndromic deafness characterized by adult onset of bilateral, postlingual, mild-to-severe sensorineural hearing loss. Sensorineural hearing loss results from damage to the neural receptors of the inner ear, the nerve pathways to the brain, or the area of the brain that receives sound information. The gene represented in this entry is involved in disease pathogenesis.

Activity regulation. MK 571 inhibits sphingosine 1-phosphate and leukotriene C4 export.

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

Isoforms (9)

UniProt ID	Names	Canonical?
P33527-1	1, Allexons	yes
P33527-2	2, Delexon-17
P33527-3	3, Delexon-18
P33527-4	4, Delexon-30
P33527-5	5, Delexon-17-18
P33527-6	6, Delexon-17-30
P33527-7	7, Delexon-18-30
P33527-8	8, Delexon-17-18-30
P33527-9	9

RefSeq proteins (2): NP_004987, NP_063915 (=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 7.6.2.2 — ABC-type xenobiotic transporter (BRENDA: 49 organisms, 716 substrates, 471 inhibitors, 280 Km, 31 kcat entries)
• 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)

75 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
ATP	0.0009–9	105
VERAPAMIL/IN	0.0006–0.0058	11
VINBLASTINE/IN	0.0002–0.1455	11
ESTRADIOL 17-BETA-D-GLUCURONIDE/IN	0.013–0.17	7
LEUKOTRIENE C4/IN	—	7
METHOTREXATE/IN	0.24–0.776	6
NICARDIPINE/IN	0.0004–0.0026	6
PROGESTERONE/IN	0.0038–0.0207	6
CYCLIC GUANOSINE MONOPHOSPHATE/IN	0.36–2	5
VERAPAMIL	0.0022–0.0115	5
ATP	0.0865–0.91	5
COLCHICINE/IN	0.037–0.72	4
FOLIC ACID/IN	0.13–0.26	4
PACLITAXEL/IN	0.0007–0.0009	4
RHODAMINE 123/IN	0.0118–0.0354	4

Catalyzed reactions (Rhea), 10 shown:

• an S-substituted glutathione(in) + ATP + H2O = an S-substituted glutathione(out) + ADP + phosphate + H(+) (RHEA:19121)
• daunorubicin(in) + ATP + H2O = daunorubicin(out) + ADP + phosphate + H(+) (RHEA:33147)
• sphing-4-enine 1-phosphate(in) + ATP + H2O = sphing-4-enine 1-phosphate(out) + ADP + phosphate + H(+) (RHEA:38951)
• leukotriene C4(in) + ATP + H2O = leukotriene C4(out) + ADP + phosphate + H(+) (RHEA:38963)
• 17beta-estradiol 17-O-(beta-D-glucuronate)(in) + ATP + H2O = 17beta-estradiol 17-O-(beta-D-glucuronate)(out) + ADP + phosphate + H(+) (RHEA:60128)
• vincristine(in) + ATP + H2O = vincristine(out) + ADP + phosphate + H(+) (RHEA:60160)
• 2’,3’-cGAMP(in) + ATP + H2O = 2’,3’-cGAMP(out) + ADP + phosphate + H(+) (RHEA:74887)
• S-[(2E,6E,10E)-geranylgeranyl]-L-glutathione(in) + ATP + H2O = S-[(2E,6E,10E)-geranylgeranyl]-L-glutathione(out) + ADP + phosphate + H(+) (RHEA:81611)
• prostaglandin A2-S-(R)-glutathione(in) + ATP + H2O = prostaglandin A2-S-(R)-glutathione(out) + ADP + phosphate + H(+) (RHEA:81695)
• prostaglandin A2-S-(S)-glutathione(in) + ATP + H2O = prostaglandin A2-S-(S)-glutathione(out) + ADP + phosphate + H(+) (RHEA:81699)

UniProt features (123 total): mutagenesis site 24, sequence variant 19, topological domain 18, transmembrane region 17, strand 11, helix 10, modified residue 6, domain 4, binding site 4, splice variant 4, glycosylation site 3, turn 2, chain 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
2CBZ	X-RAY DIFFRACTION	1.5
4C3Z	X-RAY DIFFRACTION	2.1
8VUX	ELECTRON MICROSCOPY	3.54
8VT4	ELECTRON MICROSCOPY	3.79
8VVC	ELECTRON MICROSCOPY	4.32

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P33527-F1	83.01	0.42

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 (4): 653; 678–685; 713; 1327–1334

Post-translational modifications (6): 277, 289, 503, 905, 915, 930

Glycosylation sites (3): 19, 23, 1006

Mutagenesis-validated functional residues (24):

Position	Phenotype
580	no effect.
581	no effect.
585	no effect.
597	increases resistance to vincristine and decreases resistance to vp-16.
604	increases estradiol glucuronide transport.
605	decreases resistance to vincristine, vp-16 and doxorubicin.
792	only partially affects protein maturation; impairs leukotriene c4 transport.
792	impairs protein maturation and leukotriene c4 transport.
793	no effect on protein maturation and leukotriene c4 transport.
1046	slightly impairs leukotriene c4 and estradiol glucuronide transport.
1084	impairs leukotriene c4 and estradiol glucuronide transport.
1089	decreases resistance to anthracyclines.
1089	no effect.
1089	abolishes resistance to anthracyclines.
1131	slightly impairs leukotriene c4 and estradiol glucuronide transport.
1138	strongly reduced transport of leukotriene c4, estradiol glucuronide and of glutathione.
1141	reduced transport of leukotriene c4 and of glutathione.
1141	reduced transport of glutathione.
1142	reduced transport of leukotriene c4, estradiol glucuronide and of glutathione.
1246	impairs estradiol glucuronide transport.
1246	impairs estradiol glucuronide transport; loss of resistance to alkaloid vincristine, cationic anthracyclines, epipodophy
1333	impairs leukotriene c4 transport.
1333	reduced cgamp export.
1454–1455	impairs leukotriene c4 transport.

Function

Pathways and Gene Ontology

Reactome pathways

24 pathways

ID	Pathway
R-HSA-1660661	Sphingolipid de novo biosynthesis
R-HSA-189483	Heme degradation
R-HSA-2142691	Synthesis of Leukotrienes (LT) and Eoxins (EX)
R-HSA-382556	ABC-family protein mediated transport
R-HSA-9707564	Cytoprotection by HMOX1
R-HSA-9753281	Paracetamol ADME
R-HSA-9758890	Transport of RCbl within the body
R-HSA-9818032	NFE2L2 regulating MDR associated enzymes
R-HSA-1430728	Metabolism
R-HSA-189445	Metabolism of porphyrins
R-HSA-196741	Cobalamin (Cbl, vitamin B12) transport and metabolism
R-HSA-196849	Metabolism of water-soluble vitamins and cofactors
R-HSA-196854	Metabolism of vitamins and cofactors
R-HSA-2142753	Arachidonate metabolism
R-HSA-2262752	Cellular responses to stress
R-HSA-382551	Transport of small molecules
R-HSA-428157	Sphingolipid metabolism
R-HSA-556833	Metabolism of lipids
R-HSA-8953897	Cellular responses to stimuli
R-HSA-8978868	Fatty acid metabolism
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: 436 (showing top): GOBP_MEMORY, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_EPITHELIUM_DEVELOPMENT, PID_S1P_S1P1_PATHWAY, KANG_DOXORUBICIN_RESISTANCE_UP, GOBP_COGNITION, GOBP_BEHAVIOR, MODULE_169, GOBP_CIRCULATORY_SYSTEM_PROCESS, GOBP_CELL_CHEMOTAXIS, GOBP_INFLAMMATORY_RESPONSE, GOBP_RESPONSE_TO_PEPTIDE, GCM_MSN, MODULE_151, GOBP_RESPONSE_TO_FLUID_SHEAR_STRESS

GO Biological Process (69): tissue homeostasis (GO:0001894), granuloma formation (GO:0002432), inflammatory response to antigenic stimulus (GO:0002437), endothelium development (GO:0003158), leukotriene metabolic process (GO:0006691), glutathione metabolic process (GO:0006749), xenobiotic metabolic process (GO:0006805), memory (GO:0007613), glucocorticoid metabolic process (GO:0008211), response to xenobiotic stimulus (GO:0009410), response to toxic substance (GO:0009636), gene expression (GO:0010467), cobalamin transport (GO:0015889), leukotriene biosynthetic process (GO:0019370), amygdala development (GO:0021764), hippocampus development (GO:0021766), neurogenesis (GO:0022008), sphingolipid biosynthetic process (GO:0030148), protein localization to cell surface (GO:0034394), response to fluid shear stress (GO:0034405), cellular response to oxidative stress (GO:0034599), glutathione transmembrane transport (GO:0034775), multicellular organism growth (GO:0035264), exploration behavior (GO:0035640), macrophage activation (GO:0042116), heme catabolic process (GO:0042167), regulation of membrane potential (GO:0042391), superoxide anion generation (GO:0042554), xenobiotic transport (GO:0042908), pigment accumulation (GO:0043476), phospholipid translocation (GO:0045332), cell redox homeostasis (GO:0045454), antigen processing and presentation of lipid antigen via MHC class Ib (GO:0048003), amyloid-beta metabolic process (GO:0050435), hydrogen peroxide biosynthetic process (GO:0050665), positive regulation of inflammatory response (GO:0050729), defense response to Gram-positive bacterium (GO:0050830), NK T cell activation (GO:0051132), response to glucocorticoid (GO:0051384), establishment of localization in cell (GO:0051649)

GO Molecular Function (19): ATP binding (GO:0005524), ABC-type xenobiotic transporter activity (GO:0008559), bilirubin transmembrane transporter activity (GO:0015127), ABC-type vitamin B12 transporter activity (GO:0015420), ABC-type glutathione S-conjugate transporter activity (GO:0015431), efflux transmembrane transporter activity (GO:0015562), ATP hydrolysis activity (GO:0016887), ATPase-coupled carboxylic acid transmembrane transporter activity (GO:0033284), ATPase-coupled lipid transmembrane transporter activity (GO:0034040), glutathione transmembrane transporter activity (GO:0034634), ATPase-coupled transmembrane transporter activity (GO:0042626), xenobiotic transmembrane transporter activity (GO:0042910), obsolete ATPase-coupled inorganic anion transmembrane transporter activity (GO:0043225), sphingolipid intramembrane carrier activity (GO:0046624), carboxylic acid transmembrane transporter activity (GO:0046943), ABC-type transporter activity (GO:0140359), nucleotide binding (GO:0000166), hydrolase activity (GO:0016787), transmembrane transporter activity (GO:0022857)

GO Cellular Component (7): plasma membrane (GO:0005886), basal plasma membrane (GO:0009925), membrane (GO:0016020), basolateral plasma membrane (GO:0016323), apical plasma membrane (GO:0016324), lateral plasma membrane (GO:0016328), extracellular exosome (GO:0070062)

Reactome top-level categories

Rollup of top-14 pathways:

Category	Pathways
Metabolism	3
Metabolism of lipids	2
Sphingolipid metabolism	1
Metabolism of porphyrins	1
Arachidonate metabolism	1
Transport of small molecules	1
Cellular response to chemical stress	1
Drug ADME	1
Cobalamin (Cbl, vitamin B12) transport and metabolism	1
Nuclear events mediated by NFE2L2	1
Metabolism of water-soluble vitamins and cofactors	1
Metabolism of vitamins and cofactors	1
Fatty acid metabolism	1
Cellular responses to stimuli	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
ABC-type transporter activity	3
transmembrane transporter activity	3
ATPase-coupled transmembrane transporter activity	3
plasma membrane region	3
response to chemical	2
limbic system development	2
anatomical structure development	2
sulfur compound transmembrane transporter activity	2
ATP-dependent activity	2
cellular anatomical structure	2
multicellular organismal-level homeostasis	1
anatomical structure homeostasis	1
immune effector process	1
chronic inflammatory response	1
inflammatory response	1
immune response	1
epithelium development	1
icosanoid metabolic process	1
modified amino acid metabolic process	1
sulfur compound metabolic process	1
metabolic process	1
cellular response to xenobiotic stimulus	1
learning or memory	1
steroid metabolic process	1
macromolecule biosynthetic process	1
vitamin transport	1
nitrogen compound transport	1
leukotriene metabolic process	1
icosanoid biosynthetic process	1
pallium development	1
nervous system development	1
cell differentiation	1
sphingolipid metabolic process	1
lipid biosynthetic process	1
intracellular protein localization	1
response to stress	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
xenobiotic transmembrane transporter activity	1
dicarboxylic acid transmembrane transporter activity	1

Protein interactions and networks

STRING

2742 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ABCC1	ABCG2	Q9UNQ0	969
ABCC1	MRPS7	Q9Y2R9	925
ABCC1	MVP	Q14764	691
ABCC1	LTB4R2	Q9NPC1	684
ABCC1	LTC4S	Q16873	674
ABCC1	CTNNB1	P35222	637
ABCC1	SPNS2	Q8IVW8	605
ABCC1	MYC	P01106	591
ABCC1	Q6RUI8	Q6RUI8	589
ABCC1	SLCO1B1	Q9Y6L6	588
ABCC1	CYP2B6	P20813	586
ABCC1	SLCO1A2	P46721	584
ABCC1	SLCO2B1	O94956	580
ABCC1	ABCG1	P45844	579
ABCC1	LTA4H	P09960	576

IntAct

69 interactions, top by confidence:

A	B	Type	Score
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
NIPAL1	ESYT2	psi-mi:“MI:0914”(association)	0.640
	UBXN8	psi-mi:“MI:0914”(association)	0.530
LGALS3	PODXL	psi-mi:“MI:0914”(association)	0.530
DNAJB8	DNAJB6	psi-mi:“MI:0914”(association)	0.530
GPRC5B	STXBP3	psi-mi:“MI:0914”(association)	0.530
LPAR1	TMEM223	psi-mi:“MI:0914”(association)	0.530
OPALIN	BTAF1	psi-mi:“MI:0914”(association)	0.530
pipB2	SCD	psi-mi:“MI:0914”(association)	0.460
NPM1	ABCC1	psi-mi:“MI:0915”(physical association)	0.370
AZGP1	ABCC1	psi-mi:“MI:0915”(physical association)	0.370
ABCC1	TRAF3	psi-mi:“MI:0915”(physical association)	0.370
Kcnk1	TRAPPC13	psi-mi:“MI:0914”(association)	0.350
		psi-mi:“MI:0914”(association)	0.350
	ESYT2	psi-mi:“MI:0914”(association)	0.350
E5	ESYT2	psi-mi:“MI:0914”(association)	0.350
	HAX1	psi-mi:“MI:0914”(association)	0.350
	TNFRSF10B	psi-mi:“MI:0914”(association)	0.350
CLN6	SCAMP3	psi-mi:“MI:0914”(association)	0.350
SLC15A3		psi-mi:“MI:0914”(association)	0.350
UNC93B1		psi-mi:“MI:0914”(association)	0.350
PA	DDX39A	psi-mi:“MI:0914”(association)	0.350
M	TM9SF1	psi-mi:“MI:0914”(association)	0.350
pipB2	PLOD2	psi-mi:“MI:0914”(association)	0.350
CTDP1	ESYT2	psi-mi:“MI:0914”(association)	0.350
ALCAM	LAMB1	psi-mi:“MI:0914”(association)	0.350
CMTM5	TMEM120B	psi-mi:“MI:0914”(association)	0.350

BioGRID (207): ABCC1 (Affinity Capture-Western), ABCC1 (Co-purification), ABCC1 (Co-fractionation), ABCC1 (Affinity Capture-Western), ABCC1 (Reconstituted Complex), ABCC1 (Co-fractionation), ABCC1 (Co-fractionation), ABCC1 (Co-fractionation), ABCC1 (Co-fractionation), ABCC1 (Co-fractionation), ABCC1 (Co-fractionation), ABCC1 (Co-fractionation), ABCC1 (Co-fractionation), ECHS1 (Co-fractionation), HNRNPL (Co-fractionation)

ESM2 similar proteins: A2XCD4, A7KVC2, B2RX12, G5EE72, O15440, O35379, O60706, O88563, P33527, P70170, P82451, P91660, Q07DZ6, Q07E16, Q09427, Q09428, Q09429, Q10RX7, Q1LX78, Q28689, Q2QL83, Q2QLH0, Q42093, Q5F364, Q63120, Q63563, Q6UR05, Q6Y306, Q7DM58, Q7GB25, Q80WJ6, Q864R9, Q8CG09, Q8HXQ5, Q8LGU1, Q8VI47, Q8VZZ4, Q92887, Q96J65, Q9C8G9

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

5 interactions.

A	Effect	B	Mechanism
CSNK2A1	up-regulates	ABCC1	phosphorylation
MYCN	“up-regulates quantity by expression”	ABCC1	“transcriptional regulation”
doxorubicin	“down-regulates activity”	ABCC1	“chemical inhibition”
daunorubicin	“down-regulates activity”	ABCC1	“chemical inhibition”
(S)-verapamil	“up-regulates activity”	ABCC1	“chemical activation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 89 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

GO biological processes:

GO term	Partners	Fold	FDR
adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway	5	14.2×	8e-03
positive regulation of cytosolic calcium ion concentration	7	10.6×	3e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	116
Likely pathogenic	41
Uncertain significance	277
Likely benign	37
Benign	17

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1180507	GRCh37/hg19 16p13.11(chr16:14887031-16308753)x3	Pathogenic
1341990	GRCh37/hg19 16p13.11(chr16:15551302-16194578)x1	Pathogenic
145996	GRCh38/hg38 16p13.11(chr16:14716125-16383721)x1	Pathogenic
146180	GRCh38/hg38 16p13.11-12.3(chr16:15310595-18212997)x1	Pathogenic
147644	GRCh38/hg38 16p13.11-12.3(chr16:15060830-18535437)x3	Pathogenic
148975	GRCh38/hg38 16p13.11(chr16:14816259-16431491)x1	Pathogenic
149045	GRCh38/hg38 16p13.11(chr16:14783830-16234088)x1	Pathogenic
149520	GRCh38/hg38 16p13.11(chr16:14783830-16198378)x1	Pathogenic
149523	GRCh38/hg38 16p13.11(chr16:15398450-16198378)x1	Pathogenic
149876	GRCh38/hg38 16p13.11-12.3(chr16:15457205-18212984)x1	Pathogenic
150612	GRCh38/hg38 16p13.11(chr16:14954894-16198378)x1	Pathogenic
150853	GRCh38/hg38 16p13.11-12.3(chr16:15398450-18068310)x1	Pathogenic
153310	GRCh38/hg38 16p13.11(chr16:14802528-16236815)x1	Pathogenic
153386	GRCh38/hg38 16p13.11(chr16:14772427-16298053)x1	Pathogenic
153547	GRCh38/hg38 16p13.11(chr16:14805819-16420254)x1	Pathogenic
153812	GRCh38/hg38 16p13.11(chr16:15387890-16294387)x1	Pathogenic
154123	GRCh38/hg38 16p13.11(chr16:14956111-16202043)x1	Pathogenic
154289	GRCh38/hg38 16p13.11(chr16:14803768-16400926)x1	Pathogenic
154376	GRCh38/hg38 16p13.11(chr16:14874998-16034020)x1	Pathogenic
154462	GRCh38/hg38 16p13.11-12.3(chr16:15457445-18047194)x1	Pathogenic
154755	GRCh38/hg38 16p13.11(chr16:14816356-16648337)x1	Pathogenic
154784	GRCh38/hg38 16p13.11(chr16:14816356-16431517)x1	Pathogenic
154958	GRCh38/hg38 16p13.11(chr16:15398450-16268850)x1	Pathogenic
155029	GRCh38/hg38 16p13.11(chr16:14803931-16414182)x1	Pathogenic
155163	GRCh38/hg38 16p13.11(chr16:15355839-16294739)x1	Pathogenic
160807	GRCh38/hg38 16p13.11(chr16:14816348-16100721)x1	Pathogenic
160930	GRCh38/hg38 16p13.11(chr16:14816348-16431491)x1	Pathogenic
1703611	GRCh37/hg19 16p13.11(chr16:14899676-16516109)	Pathogenic
1703612	GRCh37/hg19 16p13.11(chr16:14897625-16494783)	Pathogenic
1703613	GRCh37/hg19 16p13.11(chr16:14897372-16513267)	Pathogenic

SpliceAI

6199 predictions. Top by Δscore:

Variant	Effect	Δscore
16:15949798:GG:G	donor_gain	1.0000
16:15949799:GG:G	donor_gain	1.0000
16:15949800:G:GG	donor_gain	1.0000
16:16007810:TCGCA:T	acceptor_loss	1.0000
16:16007811:CGCAG:C	acceptor_loss	1.0000
16:16007812:GCAGG:G	acceptor_loss	1.0000
16:16007813:CAGGA:C	acceptor_loss	1.0000
16:16007814:A:AG	acceptor_gain	1.0000
16:16007814:AG:A	acceptor_gain	1.0000
16:16007814:AGGAC:A	acceptor_loss	1.0000
16:16007815:G:GA	acceptor_gain	1.0000
16:16007815:G:T	acceptor_loss	1.0000
16:16007815:GG:G	acceptor_gain	1.0000
16:16007815:GGACT:G	acceptor_gain	1.0000
16:16007988:AAACT:A	donor_gain	1.0000
16:16007989:AACT:A	donor_gain	1.0000
16:16007990:ACT:A	donor_gain	1.0000
16:16007993:G:GG	donor_gain	1.0000
16:16009900:TGGT:T	donor_loss	1.0000
16:16009901:GGT:G	donor_loss	1.0000
16:16009902:G:GG	donor_gain	1.0000
16:16009902:G:T	donor_loss	1.0000
16:16009903:TAA:T	donor_loss	1.0000
16:16033169:GG:G	donor_gain	1.0000
16:16033170:GG:G	donor_gain	1.0000
16:16036600:GGAA:G	donor_gain	1.0000
16:16036601:GAA:G	donor_gain	1.0000
16:16036601:GAAG:G	donor_gain	1.0000
16:16036603:AG:A	donor_loss	1.0000
16:16036604:G:C	donor_loss	1.0000

AlphaMissense

10047 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
16:16048200:T:C	L426P	0.999
16:16048256:T:A	W445R	0.999
16:16048256:T:C	W445R	0.999
16:16056120:G:C	R501P	0.999
16:16068253:T:C	L592P	0.999
16:16083396:T:A	W716R	0.999
16:16083396:T:C	W716R	0.999
16:16122081:G:C	R1166P	0.999
16:16134362:G:A	G1327R	0.999
16:16134362:G:C	G1327R	0.999
16:16134362:G:T	G1327W	0.999
16:16134363:G:A	G1327E	0.999
16:16134363:G:T	G1327V	0.999
16:16134374:G:C	A1331P	0.999
16:16134380:A:C	K1333Q	0.999
16:16134381:A:T	K1333M	0.999
16:16134508:G:C	Q1375H	0.999
16:16134508:G:T	Q1375H	0.999
16:16138390:T:C	L1440P	0.999
16:16138432:A:C	D1454A	0.999
16:16138432:A:T	D1454V	0.999
16:16138434:G:A	E1455K	0.999
16:16138435:A:C	E1455A	0.999
16:16138435:A:G	E1455G	0.999
16:16138435:A:T	E1455V	0.999
16:16138436:G:C	E1455D	0.999
16:16138436:G:T	E1455D	0.999
16:16138443:G:C	A1458P	0.999
16:16138525:C:A	A1485D	0.999
16:16138527:C:G	H1486D	0.999

dbSNP variants (sampled 300 via entrez): RS1000005772 (16:16052373 A>G), RS1000006657 (16:16017300 G>A), RS1000006910 (16:16141976 G>C), RS1000010834 (16:16079721 A>C,G), RS1000045156 (16:15993849 C>G,T), RS1000046042 (16:16109961 T>G), RS1000070382 (16:16123470 A>G), RS1000074669 (16:16093592 C>A), RS1000087051 (16:16004194 A>T), RS1000114508 (16:15964235 G>A,T), RS1000114966 (16:16003968 G>A), RS1000115441 (16:16058214 A>G,T), RS1000135407 (16:16103489 A>G), RS1000140722 (16:16137790 C>T), RS1000146481 (16:15970079 A>G)

Disease associations

OMIM: gene MIM:158343 | disease phenotypes: MIM:114480, MIM:619351, MIM:251450, MIM:209850, MIM:124900, MIM:264800, MIM:181500, MIM:193250, MIM:610543, MIM:618915

GenCC curated gene-disease

Disease	Classification	Inheritance
hearing loss, autosomal dominant 77	Moderate	Autosomal dominant
autosomal dominant nonsyndromic hearing loss	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
autosomal dominant nonsyndromic hearing loss	Limited	AD

Mondo (16): hereditary breast carcinoma (MONDO:0016419), megacystis-microcolon-intestinal hypoperistalsis syndrome 2 (MONDO:0025708), Desbuquois dysplasia 1 (MONDO:0009629), autism (MONDO:0005260), hydrocephalus (MONDO:0001150), 16p13.11 microdeletion syndrome (MONDO:0016836), 16p13.11 microduplication syndrome (MONDO:0016837), autism spectrum disorder (MONDO:0005258), autosomal dominant nonsyndromic hearing loss (MONDO:0019587), autosomal recessive inherited pseudoxanthoma elasticum (MONDO:0009925), schizophrenia (MONDO:0005090), volvulus of midgut (MONDO:0008666), Rubinstein-Taybi syndrome due to 16p13.3 microdeletion (MONDO:0012519), hearing loss, autosomal dominant 77 (MONDO:0030058), epilepsy (MONDO:0005027)

Orphanet (13): Hereditary breast cancer (Orphanet:227535), Desbuquois syndrome (Orphanet:1425), 16p13.11 microdeletion syndrome (Orphanet:261236), 16p13.11 microduplication syndrome (Orphanet:261243), Rare autosomal dominant non-syndromic sensorineural deafness type DFNA (Orphanet:90635), Pseudoxanthoma elasticum (Orphanet:758), OBSOLETE: Familial intestinal malrotation-facial anomalies syndrome (Orphanet:2454), Familial intestinal malrotation (Orphanet:508410), Rubinstein-Taybi syndrome due to 16p13.3 microdeletion (Orphanet:353281), Rubinstein-Taybi syndrome (Orphanet:783), NON RARE IN EUROPE: Autism (Orphanet:106), NON RARE IN EUROPE: Schizophrenia (Orphanet:3140), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

5 total (7 of 5 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000360	Tinnitus
HP:0000407	Sensorineural hearing impairment
HP:0003581	Adult onset
HP:0011390	Abnormal inner ear morphology
HP:0000717	Autism
HP:0100753	Schizophrenia

GWAS associations

22 associations (top):

Study	Trait	p-value
GCST003051_1	Multiple myeloma (survival)	7.000000e-09
GCST003225_26	Pelvic organ prolapse (moderate/severe)	3.000000e-07
GCST003261_1	Ischemic stroke (undetermined subtype)	5.000000e-11
GCST004068_52	Venous thromboembolism adjusted for sickle cell variant rs77121243-T	6.000000e-06
GCST004618_19	White blood cell count (basophil)	1.000000e-10
GCST004685_3	Psychosis proneness (perceptual aberration scale)	4.000000e-06
GCST008058_4	Estimated glomerular filtration rate	4.000000e-10
GCST009557_1	Rate of ventricular enlargement	9.000000e-06
GCST010579_5	Response to antiepileptic mood-stabilizing treatment in bipolar disorder	2.000000e-06
GCST012020_127	Serum metabolite levels	4.000000e-27
GCST012020_463	Serum metabolite levels	6.000000e-15
GCST90002379_74	Basophil count	1.000000e-15
GCST90002380_36	Basophil percentage of white cells	1.000000e-13
GCST90002390_80	Mean corpuscular hemoglobin	8.000000e-10
GCST90002391_75	Mean corpuscular hemoglobin concentration	3.000000e-09
GCST90002396_579	Mean reticulocyte volume	3.000000e-14
GCST90002396_580	Mean reticulocyte volume	2.000000e-11
GCST90002397_232	Mean spheric corpuscular volume	3.000000e-13
GCST90002397_233	Mean spheric corpuscular volume	6.000000e-11
GCST90002404_336	Red cell distribution width	3.000000e-11
GCST90020028_1491	Hip circumference adjusted for BMI	7.000000e-09
GCST90026412_11	Severe autoimmune type 2 diabetes	7.000000e-06

EFO canonical traits (10, from GWAS)

EFO ID	Trait name
EFO:0000638	overall survival
EFO:0005090	basophil count
EFO:0008337	psychosis predisposition measurement
EFO:0010570	ventricular enlargement measurement
EFO:0007992	basophil percentage of leukocytes
EFO:0004527	mean corpuscular hemoglobin
EFO:0004528	mean corpuscular hemoglobin concentration
EFO:0010701	mean reticulocyte volume
EFO:0009188	Red cell distribution width
EFO:0008039	BMI-adjusted hip circumference

MeSH disease descriptors (7)

Descriptor	Name	Tree numbers
D001321	Autistic Disorder	F03.625.164.113.500
D004827	Epilepsy	C10.228.140.490
D006849	Hydrocephalus	C10.228.140.602
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D011561	Pseudoxanthoma Elasticum	C14.907.454.530; C15.378.463.515.530; C16.131.831.766; C16.320.850.750; C17.300.766; C17.800.804.766; C17.800.827.750
C562840	Breast Cancer, Familial (supp.)
C562456	Volvulus Of Midgut (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL3004 (SINGLE PROTEIN), CHEMBL3430875 (SELECTIVITY GROUP)

Molecules with ChEMBL bioactivity

23 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 1,908,965 (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
CHEMBL111	RIMONABANT	4	15,726
CHEMBL159	VINBLASTINE	4	412,636
CHEMBL160	CYCLOSPORINE	4	168,247
CHEMBL178	DAUNORUBICIN	4	203,756
CHEMBL308954	ETRAVIRINE	4	11,287
CHEMBL388590	BENZBROMARONE	4	8,245
CHEMBL494753	ESTRONE SULFURIC ACID	4	3,380
CHEMBL53463	DOXORUBICIN	4	314,282
CHEMBL58	MITOXANTRONE	4	166,878
CHEMBL6	INDOMETHACIN	4	156,366
CHEMBL6067487	IVERMECTIN	4
CHEMBL6966	VERAPAMIL	4	75,097
CHEMBL90555	VINCRISTINE	4	268,031
CHEMBL1086218	VALSPODAR	3	5,970
CHEMBL348475	TARIQUIDAR	3	3,984
CHEMBL50	QUERCETIN	3	74,559
CHEMBL197	DEXVERAPAMIL	2	15,079
CHEMBL2013174	VEDROPREVIR	2	314
CHEMBL280481	VERLUKAST	2	2,491
CHEMBL350775	BIRICODAR	2	2,637
CHEMBL4567446	CLESACOSTAT	2
CHEMBL575448	BMS-754807	2
CHEMBL150	KAEMPFEROL	1

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

PharmGKB clinical annotations

14 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs119774	Efficacy	3	montelukast	Asthma
rs17501331	Toxicity	3	irinotecan	Colorectal Neoplasms;Neutropenia
rs212091	Efficacy	3	lamivudine;lopinavir;ritonavir;zidovudine	HIV infectious disease
rs2238476	Efficacy,Toxicity	3	methotrexate	Psoriasis
rs246240	Toxicity	3	methotrexate	Drug Toxicity;Psoriasis
rs246240	Efficacy	3	methotrexate	Rheumatoid arthritis
rs28364006	Efficacy	3	methotrexate	Psoriasis
rs35592	Efficacy	3	methotrexate	Psoriasis;Rheumatoid arthritis
rs35621	Metabolism/PK	3	SN-38	Colorectal Neoplasms
rs3743527	Toxicity	3	irinotecan	Colorectal Neoplasms
rs3784864	Efficacy	3	methotrexate	Rheumatoid arthritis
rs4148350	Toxicity	4	anthracyclines and related substances	Neoplasms
rs45511401	Toxicity	3	doxorubicin	Cardiac rhythm disease;Drug Toxicity;Non-Hodgkin Lymphoma
rs6498588	Metabolism/PK	3	SN-38	Colorectal Neoplasms

PharmGKB variants

45 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs35592	ABCC1	3	1.75	1	methotrexate
rs35596	ABCC1		0.00	0
rs119774	ABCC1	3	2.25	1	montelukast
rs212091	ABCC1	3	2.25	1	lamivudine;lopinavir;ritonavir;zidovudine
rs246221	ABCC1		0.00	0
rs246240	ABCC1	3	3.00	2	methotrexate
rs903880	ABCC1		0.00	0
rs2074087	ABCC1		0.00	0
rs2238476	ABCC1	3	4.50	1	methotrexate
rs2889517	ABCC1		0.00	0
rs3743527	ABCC1	3	1.75	1	irinotecan
rs3784862	ABCC1		0.00	0
rs3784864	ABCC1	3	2.50	1	methotrexate
rs4148350	ABCC1	4	-1.75	1	anthracyclines and related substances
rs4148354	ABCC1		0.00	0
rs4148356	ABCC1		0.00	0
rs4781712	ABCC1		0.00	0
rs8058040	ABCC1		0.00	0
rs11861115	ABCC1		0.00	0
rs16967126	ABCC1		0.00	0
rs17264736	ABCC1		0.00	0
rs17287570	ABCC1		0.00	0
rs28364006	ABCC1	3	2.25	1	methotrexate
rs35529209	ABCC1		0.00	0
rs45511401	ABCC1	3	3.25	1	doxorubicin
rs1967120	ABCC1		0.00	0
rs35621	ABCC1	3	1.25	1	SN-38
rs8187843	ABCC1		0.00	0
rs215095	ABCC1		0.00	0
rs212082	ABCC1		0.00	0
rs17501331	ABCC1	3	1.75	1	irinotecan
rs212090	ABCC1		0.00	0
rs35626	ABCC1		0.00	0
rs152023	ABCC1		0.00	0
rs11075291	ABCC1		0.00	0
rs3784867	ABCC1		0.00	0
rs17501011	ABCC1		0.00	0
rs4148333	ABCC1		0.00	0
rs4781701	ABCC1		0.00	0
rs12934692	ABCC1		0.00	0

GtoPdb / IUPHAR curated pharmacology

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

Target class: transporter — ABCC subfamily

Most potent curated ligand interactions (3 total), top 3:

Ligand	Action	Affinity	Parameter
WP814	Inhibition	7.15	pKi
compound 14 [PMID: 30925062]	Competitive	5.3	pIC50
biricodar	Inhibition	5.29	pIC50

Binding affinities (BindingDB)

779 measured of 805 human assays (817 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
7-(difluoromethyl)-3-[(2-ethyl-1H-imidazol-1-yl)carbonyl]-5-(4-methylphenyl)pyrazolo[1,5-a]pyrimidine	EC50	523 nM
3-(phenylmethyl)-5-[1-(phenylsulfonyl)piperidin-3-yl]-2H-[1,2,3]triazolo[4,5-d]pyrimidin-7-one	EC50	603 nM
MLS000696981	EC50	631 nM
2,3-Dihydro-benzo[1,4]dioxine-2-carboxylic acid [1-(2-hydroxy-3-methoxy-phenyl)-meth-(E)-ylidene-hydrazinocarbonylmethyl]-amide	EC50	637 nM
10H-pyrazino[2,3-b][1,4]benzothiazine	EC50	637 nM
2-(3,5-dimethyl-1-pyrazolyl)-N-[(4-methoxyphenyl)methylideneamino]-6-methyl-4-pyrimidinamine	EC50	656 nM
(3,5-Dimethyl-4-nitro-pyrazol-1-yl)-acetic acid [1-(2-hydroxy-3-methoxy-phenyl)-meth-(E)-ylidene]-hydrazide	EC50	673 nM
4-(1-oxoheptylamino)-N-(3-pyridinylmethylideneamino)benzamide	EC50	694 nM
Benzoic acid 4-bromo-2-[(5-methyl-2H-pyrazole-3-carbonyl)-hydrazonomethyl]-phenyl ester	EC50	808 nM
(4E)-4-[[2-[2-(3,5-dimethylpyrazol-1-yl)-6-methyl-pyrimidin-4-yl]hydrazinyl]methylidene]-3-oxidanyl-cyclohexa-2,5-dien-1-one	EC50	831 nM
3-[N’-[(E)-(2-hydroxy-4-keto-cyclohexa-2,5-dien-1-ylidene)methyl]hydrazino]-6-veratryl-2H-1,2,4-triazin-5-one	EC50	836 nM
2-(7-chloranyl-2-oxidanylidene-5-phenyl-3H-1,4-benzodiazepin-1-yl)-N-[4-(dimethylamino)phenyl]ethanamide	IC50	856 nM
1,3-dimethyl-8-[(2-methyl-1-piperidinyl)methyl]-7-pentylpurine-2,6-dione	EC50	883 nM
(4-Benzhydryl-piperazin-1-yl)-(5-thiophen-2-yl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidin-3-yl)-methanone	EC50	916 nM
2-[4-(5-chloranyl-2-methyl-phenyl)piperazin-1-yl]carbonyl-1,5-dimethyl-pyrrolo[3,2-c]quinolin-4-one	EC50	1000 nM
MLS000723318	EC50	1010 nM
1-(2-Diethylamino-ethyl)-1-(6,8-dimethyl-2-oxo-1,2-dihydro-quinolin-3-ylmethyl)-3-furan-2-ylmethyl-thiourea	EC50	1030 nM
2-N-benzyl-4-N-[(2-chlorophenyl)methylideneamino]-6-methylpyrimidine-2,4-diamine	EC50	1080 nM
MLS000324799	EC50	1090 nM
2-[[1-oxo-2-(1H-1,2,4-triazol-5-ylthio)ethyl]amino]-4-thiophen-2-yl-3-thiophenecarboxylic acid ethyl ester	EC50	1090 nM
3-Amino-2-(4-methoxy-benzoyl)-4-(4-methoxycarbonyl-phenyl)-6-methyl-4,7-dihydro-thieno[2,3-b]pyridine-5-carboxylic acid ethyl ester	EC50	1100 nM
1-[bis(4-morpholinyl)phosphoryl]-N’-(4-methoxyphenyl)-N-(4-nitroanilino)methanimidamide	EC50	1120 nM
(Z)-3-(4-hydroxyanilino)-2-nitro-2-propenoic acid methyl ester	EC50	1120 nM
8-[2-(4-Methoxy-phenyl)-5-phenyl-pyrazolo[1,5-a]pyrimidin-7-yl]-1,4-dioxa-8-aza-spiro[4.5]decane	EC50	1160 nM
1,6,6-triphenyl-3-(p-tolyl)-3-azabicyclo[3.1.0]hexane-2,4-quinone	EC50	1160 nM
2-[[3-(4-methoxyphenyl)-4-oxidanylidene-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl]sulfanyl]-N-phenyl-ethanamide	EC50	1180 nM
3-phenyl-N-(5-tetralin-6-yl-1,3,4-oxadiazol-2-yl)propionamide	EC50	1360 nM
2-[(4-morpholin-4-yl-1,2,5-thiadiazol-3-yl)oxy]-N’-[(E)-(6-oxidanylidenecyclohexa-2,4-dien-1-ylidene)methyl]ethanehydrazide	EC50	1390 nM
(6Z)-3-methoxy-6-[4-(1-phenyl-4-pyrazolyl)-1,2-dihydropyrazol-3-ylidene]-1-cyclohexa-2,4-dienone	EC50	1430 nM
1-[(5-bromanyl-2-oxidanylidene-indol-3-yl)amino]-3-(1,5-dimethyl-3-oxidanylidene-2-phenyl-pyrazol-4-yl)thiourea	EC50	1480 nM
(3-bromanylimidazo[1,2-a]pyridin-2-yl)methyl carbamimidothioate;hydrobromide	EC50	1490 nM
1-[oxo-[3-(1-pyrrolyl)-2-thiophenyl]methyl]-N-(4-phenylbutan-2-yl)-4-piperidinecarboxamide	EC50	1500 nM
4-[4-(2,4-dimethoxyphenyl)-3-methyl-6-oxo-2,4-dihydropyrrolo[3,4-c]pyrazol-5-yl]benzoic acid ethyl ester	EC50	1510 nM
6-chloranyl-2-[2-(2,5-dimethylpyrrol-1-yl)thiophen-3-yl]-5-methyl-1H-pyrazolo[1,5-a]pyrimidin-7-one	IC50	1530 nM
3-(3,5-Dimethyl-pyrazol-1-yl)-propionic acid [1-(2-hydroxy-phenyl)-meth-(E)-ylidene]-hydrazide	EC50	1540 nM
(4E)-2-(1,3-thiazol-2-yl)-4-[(2,4,6-trimethylanilino)methylidene]isoquinoline-1,3-dione	EC50	1540 nM
MLS000545573	EC50	1600 nM
4-(6-keto-2,4-dihydrothiazolo[3,2-a][1,3,5]triazin-3-yl)benzoic acid ethyl ester	EC50	1600 nM
2-(cyanomethylsulfanyl)-6-ethoxy-quinoline-3-carbonitrile	EC50	1620 nM
4-Amino-isothiazole-3,5-dicarboxylic acid 3-amide 5-{(2-ethoxy-phenyl)-[furan-2-yl-(3-methyl-butylcarbamoyl)-methyl]-amide}	EC50	1620 nM
2-Cyclopropyl-4-[4-(4-fluoro-benzenesulfonyl)-piperazin-1-yl]-5,6-dimethyl-thieno[2,3-d]pyrimidine	EC50	1630 nM
5-[4-(dimethylamino)phenyl]imino-1-(2-hydroxyethyl)-2,6-diketo-4-methyl-nicotinonitrile	EC50	1630 nM
4-[(5Z)-4-keto-5-(4-methylbenzylidene)-2-thioxo-thiazolidin-3-yl]-N-thiazol-2-yl-butyramide	EC50	1640 nM
4-(4-methyl-1-piperidinyl)-1-phenylpyrazolo[3,4-d]pyrimidine	EC50	1650 nM
1,3-Dimethyl-8-morpholin-4-ylmethyl-7-phenethyl-3,7-dihydro-purine-2,6-dione	EC50	1680 nM
MLS000528647	EC50	1700 nM
2-[2-[4-(2-hydroxy-3-phenoxy-propyl)piperazino]ethyl]benzo[de]isoquinoline-1,3-quinone	EC50	1710 nM
4,5-dimethyl-2-[[1-oxo-2-(1H-1,2,4-triazol-5-ylthio)ethyl]amino]-3-thiophenecarboxylic acid ethyl ester	EC50	1740 nM
2-(3,5-Dimethyl-4-nitro-pyrazol-1-yl)-propionic acid [1-(2-hydroxy-3-methoxy-phenyl)-meth-(E)-ylidene]-hydrazide	EC50	1770 nM
3-amino-6-(2-furanyl)-N-(2-methoxyphenyl)-2-thieno[2,3-b]pyridinecarboxamide	IC50	1790 nM

ChEMBL bioactivities

550 potent at pChembl≥5 of 723 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.82	IC50	1.5	nM	MITOXANTRONE
8.72	IC50	1.9	nM	MITOXANTRONE
8.00	IC50	10	nM	CHEMBL28629
8.00	IC50	10	nM	CHEMBL281496
7.96	IC50	11	nM	CHEMBL26779
7.92	IC50	12	nM	CHEMBL26150
7.92	IC50	12	nM	CHEMBL25903
7.89	IC50	13	nM	CHEMBL25905
7.86	IC50	13.7	nM	CHEMBL29743
7.82	IC50	15	nM	CHEMBL281326
7.77	IC50	17	nM	CHEMBL418382
7.72	IC50	19	nM	CHEMBL284024
7.70	IC50	20	nM	CHEMBL283255
7.68	IC50	21	nM	CHEMBL27007
7.62	IC50	24	nM	CHEMBL26678
7.62	IC50	24	nM	CHEMBL430724
7.58	IC50	26.5	nM	CHEMBL29631
7.57	IC50	27	nM	CHEMBL283253
7.56	IC50	27.5	nM	MITOXANTRONE
7.55	IC50	28	nM	CHEMBL25731
7.54	IC50	29	nM	CHEMBL439727
7.48	IC50	33	nM	CHEMBL27007
7.46	Kd	35	nM	DEXVERAPAMIL
7.42	IC50	38	nM	CHEMBL200216
7.39	IC50	41	nM	CHEMBL27415
7.39	IC50	40.9	nM	CHEMBL285343
7.37	IC50	43	nM	CHEMBL27102
7.36	IC50	44	nM	CHEMBL430724
7.35	IC50	45	nM	CHEMBL27536
7.35	IC50	45	nM	CHEMBL286948
7.32	IC50	48	nM	CHEMBL26081
7.29	IC50	51	nM	CHEMBL25867
7.28	EC50	53	nM	CHEMBL4286793
7.23	IC50	59	nM	CHEMBL27257
7.23	IC50	59	nM	CHEMBL282156
7.22	Ki	60	nM	CHEMBL2074989
7.21	IC50	61	nM	CHEMBL26485
7.21	IC50	62	nM	CHEMBL26678
7.20	IC50	63	nM	CHEMBL284676
7.19	IC50	65	nM	CHEMBL283438
7.18	IC50	66	nM	CHEMBL5436972
7.17	IC50	67	nM	CHEMBL287400
7.16	Ki	70	nM	DAUNORUBICIN
7.15	IC50	71	nM	CHEMBL28629
7.14	EC50	73	nM	CHEMBL539987
7.12	IC50	76	nM	CHEMBL280981
7.11	EC50	78	nM	CHEMBL4282529
7.11	IC50	78	nM	CHEMBL26039
7.11	IC50	78	nM	CHEMBL27191
7.10	IC50	79	nM	VERAPAMIL

PubChem BioAssay actives

557 with measured affinity, of 2615 total; 50 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
Mitoxantrone	681514: TP_TRANSPORTER: cell accumulation in MCF7/MRP1-M6 cells	ic50	0.0015	uM
6-[4-[2-(3,4-difluorophenyl)ethyl]piperazin-1-yl]-8-methyl-4-(morpholin-4-ylmethyl)-3,5,8,10-tetrazatricyclo[7.4.0.02,7]trideca-1(13),2(7),3,5,9,11-hexaene-13-carboxamide	106553: Inhibitory activity against MRP1 (Multidrug resistance associated protein 1) expressed in COR.L23/R cell line in single-dose potentiation assay	ic50	0.0100	uM
4-[6-[4-[2-(3,4-difluorophenyl)ethyl]piperazin-1-yl]-8-methyl-3,5,8,12-tetrazatricyclo[7.4.0.02,7]trideca-1(9),2(7),3,5,10,12-hexaen-13-yl]morpholine	106553: Inhibitory activity against MRP1 (Multidrug resistance associated protein 1) expressed in COR.L23/R cell line in single-dose potentiation assay	ic50	0.0100	uM
6-[4-[2-(3,4-difluorophenyl)ethyl]piperazin-1-yl]-8,11-dimethyl-12-nitro-3,5,8,10-tetrazatricyclo[7.4.0.02,7]trideca-1(13),2(7),3,5,9,11-hexaene-13-carboxamide	106553: Inhibitory activity against MRP1 (Multidrug resistance associated protein 1) expressed in COR.L23/R cell line in single-dose potentiation assay	ic50	0.0110	uM
6-[4-[2-(3,4-difluorophenyl)ethyl]piperazin-1-yl]-8-methyl-3,5,8,10-tetrazatricyclo[7.4.0.02,7]trideca-1(13),2(7),3,5,9,11-hexaene-13-carboxamide	106553: Inhibitory activity against MRP1 (Multidrug resistance associated protein 1) expressed in COR.L23/R cell line in single-dose potentiation assay	ic50	0.0120	uM
6-[4-[2-(3,4-difluorophenyl)ethyl]piperazin-1-yl]-N,N,8-trimethyl-3,5,8,12-tetrazatricyclo[7.4.0.02,7]trideca-1(9),2(7),3,5,10,12-hexaen-13-amine	106553: Inhibitory activity against MRP1 (Multidrug resistance associated protein 1) expressed in COR.L23/R cell line in single-dose potentiation assay	ic50	0.0120	uM
13-chloro-6-[4-[2-(3,4-difluorophenyl)ethyl]piperazin-1-yl]-4-(methoxymethyl)-8-methyl-3,5,8,12-tetrazatricyclo[7.4.0.02,7]trideca-1(9),2(7),3,5,10,12-hexaene	106553: Inhibitory activity against MRP1 (Multidrug resistance associated protein 1) expressed in COR.L23/R cell line in single-dose potentiation assay	ic50	0.0130	uM
4-[4-[2-(3,4-difluorophenyl)ethyl]piperazin-1-yl]-9-nitro-5-(pyridin-4-ylmethyl)pyrimido[5,4-b]indole	106553: Inhibitory activity against MRP1 (Multidrug resistance associated protein 1) expressed in COR.L23/R cell line in single-dose potentiation assay	ic50	0.0137	uM
6-[4-[2-(3,4-difluorophenyl)ethyl]piperazin-1-yl]-8-methyl-N-(pyridin-2-ylmethyl)-3,5,8,12-tetrazatricyclo[7.4.0.02,7]trideca-1(9),2(7),3,5,10,12-hexaen-13-amine	106553: Inhibitory activity against MRP1 (Multidrug resistance associated protein 1) expressed in COR.L23/R cell line in single-dose potentiation assay	ic50	0.0150	uM
4-[[13-chloro-6-[4-[2-(3,4-difluorophenyl)ethyl]piperazin-1-yl]-8-methyl-3,5,8,12-tetrazatricyclo[7.4.0.02,7]trideca-1(9),2(7),3,5,10,12-hexaen-4-yl]methyl]morpholine	106553: Inhibitory activity against MRP1 (Multidrug resistance associated protein 1) expressed in COR.L23/R cell line in single-dose potentiation assay	ic50	0.0170	uM
4-[[4-[4-[2-(3,4-difluorophenyl)ethyl]piperazin-1-yl]-6,8-dinitro-5H-pyrimido[5,4-b]indol-2-yl]methyl]morpholine	106553: Inhibitory activity against MRP1 (Multidrug resistance associated protein 1) expressed in COR.L23/R cell line in single-dose potentiation assay	ic50	0.0190	uM
4-[4-[2-(3,4-difluorophenyl)ethyl]piperazin-1-yl]-5-(pyridin-4-ylmethyl)pyrimido[5,4-b]indole-9-carboxamide	106553: Inhibitory activity against MRP1 (Multidrug resistance associated protein 1) expressed in COR.L23/R cell line in single-dose potentiation assay	ic50	0.0200	uM
6-[4-[2-(3,4-difluorophenyl)ethyl]piperazin-1-yl]-8,13-dimethyl-3,5,8,12-tetrazatricyclo[7.4.0.02,7]trideca-1(9),2(7),3,5,10,12-hexaene	106553: Inhibitory activity against MRP1 (Multidrug resistance associated protein 1) expressed in COR.L23/R cell line in single-dose potentiation assay	ic50	0.0210	uM
6-[4-[2-(3,4-difluorophenyl)ethyl]piperazin-1-yl]-8-methyl-3,5,8,12-tetrazatricyclo[7.4.0.02,7]trideca-1(9),2(7),3,5,10,12-hexaene	106553: Inhibitory activity against MRP1 (Multidrug resistance associated protein 1) expressed in COR.L23/R cell line in single-dose potentiation assay	ic50	0.0240	uM
4-[4-[2-(3,4-difluorophenyl)ethyl]piperazin-1-yl]-5-methylpyrimido[5,4-b]indole-9-carboxamide	106553: Inhibitory activity against MRP1 (Multidrug resistance associated protein 1) expressed in COR.L23/R cell line in single-dose potentiation assay	ic50	0.0240	uM
4-[4-[2-(3,4-difluorophenyl)ethyl]piperazin-1-yl]-9-nitro-5-(pyridin-3-ylmethyl)pyrimido[5,4-b]indole	106553: Inhibitory activity against MRP1 (Multidrug resistance associated protein 1) expressed in COR.L23/R cell line in single-dose potentiation assay	ic50	0.0265	uM
6-[4-[2-(3,4-difluorophenyl)ethyl]piperazin-1-yl]-8-methyl-13-propan-2-yloxy-3,5,8,12-tetrazatricyclo[7.4.0.02,7]trideca-1(9),2(7),3,5,10,12-hexaene	106553: Inhibitory activity against MRP1 (Multidrug resistance associated protein 1) expressed in COR.L23/R cell line in single-dose potentiation assay	ic50	0.0270	uM
6-[4-[2-(3,4-difluorophenyl)ethyl]piperazin-1-yl]-N,8-dimethyl-3,5,8,12-tetrazatricyclo[7.4.0.02,7]trideca-1(9),2(7),3,5,10,12-hexaen-13-amine	106553: Inhibitory activity against MRP1 (Multidrug resistance associated protein 1) expressed in COR.L23/R cell line in single-dose potentiation assay	ic50	0.0280	uM
4-[4-[2-(3,4-difluorophenyl)ethyl]piperazin-1-yl]-5-methyl-2-(morpholin-4-ylmethyl)pyrimido[5,4-b]indole-9-carboxamide	106553: Inhibitory activity against MRP1 (Multidrug resistance associated protein 1) expressed in COR.L23/R cell line in single-dose potentiation assay	ic50	0.0290	uM
(2R)-2-(3,4-dimethoxyphenyl)-5-[2-(3,4-dimethoxyphenyl)ethyl-methylamino]-2-propan-2-ylpentanenitrile	360088: Binding activity to human MRP1 expressed in BHK21 cells	kd	0.0350	uM
N-[[(1R,3S)-3-(9-chloro-3-methyl-4-oxo-[1,2]oxazolo[4,3-c]quinolin-5-yl)cyclohexyl]methyl]benzamide	257276: Inhibitory activity against MRP1-mediated LTC4 uptake into membrane vesicles from HeLa-T5 cells expressing MRP1	ic50	0.0380	uM
4-[4-[2-(3,4-difluorophenyl)ethyl]piperazin-1-yl]-9-nitro-5-(2-phenylethyl)pyrimido[5,4-b]indole	106553: Inhibitory activity against MRP1 (Multidrug resistance associated protein 1) expressed in COR.L23/R cell line in single-dose potentiation assay	ic50	0.0409	uM
13-chloro-6-[4-[2-(3,4-difluorophenyl)ethyl]piperazin-1-yl]-8-methyl-3,5,8,12-tetrazatricyclo[7.4.0.02,7]trideca-1(9),2(7),3,5,10,12-hexaene	106553: Inhibitory activity against MRP1 (Multidrug resistance associated protein 1) expressed in COR.L23/R cell line in single-dose potentiation assay	ic50	0.0410	uM
4-[4-[2-(3,4-difluorophenyl)ethyl]piperazin-1-yl]-N-[(2,3-dimethoxyphenyl)methyl]-6,7,8,9-tetrahydropyrimido[4,5-b]indolizine-10-carboxamide	106552: Inhibitory activity against human transporter MRP1 (Multidrug resistance associated protein 1) expressed in COR.L23/R cell line	ic50	0.0430	uM
6-[4-[2-(3,4-difluorophenyl)ethyl]piperazin-1-yl]-8-methyl-3,5,8,10-tetrazatricyclo[7.4.0.02,7]trideca-1(13),2(7),3,5,9,11-hexaene-13-carbonitrile	106553: Inhibitory activity against MRP1 (Multidrug resistance associated protein 1) expressed in COR.L23/R cell line in single-dose potentiation assay	ic50	0.0450	uM
ethyl 9-carbamoyl-4-[4-[2-(3,4-difluorophenyl)ethyl]piperazin-1-yl]pyrimido[5,4-b]indole-5-carboxylate	106553: Inhibitory activity against MRP1 (Multidrug resistance associated protein 1) expressed in COR.L23/R cell line in single-dose potentiation assay	ic50	0.0450	uM
8-benzyl-6-[4-[2-(3,4-difluorophenyl)ethyl]piperazin-1-yl]-3,5,8,12-tetrazatricyclo[7.4.0.02,7]trideca-1(9),2(7),3,5,10,12-hexaene	106553: Inhibitory activity against MRP1 (Multidrug resistance associated protein 1) expressed in COR.L23/R cell line in single-dose potentiation assay	ic50	0.0480	uM
4-[4-[2-(3,4-difluorophenyl)ethyl]piperazin-1-yl]-8-nitro-5H-pyrimido[5,4-b]indole	106553: Inhibitory activity against MRP1 (Multidrug resistance associated protein 1) expressed in COR.L23/R cell line in single-dose potentiation assay	ic50	0.0510	uM
7-[2-[2-[4-[3-[4-(7-fluoro-4-oxochromen-2-yl)phenoxy]propyl]triazol-1-yl]ethoxy]ethoxy]-2-phenylchromen-4-one	1414427: Inhibition of MRP1 in human 2008/MRP1 cells assessed as potentiation of doxorubicin-induced cytotoxicity by measuring reduction in cell survival after 5 days by MTS assay	ec50	0.0530	uM
methyl 4-[4-[2-(3,4-difluorophenyl)ethyl]piperazin-1-yl]-5H-pyrimido[5,4-b]indole-8-carboxylate	106553: Inhibitory activity against MRP1 (Multidrug resistance associated protein 1) expressed in COR.L23/R cell line in single-dose potentiation assay	ic50	0.0590	uM
4-[4-[2-(3,4-difluorophenyl)ethyl]piperazin-1-yl]-9-nitro-5H-pyrimido[5,4-b]indole	106553: Inhibitory activity against MRP1 (Multidrug resistance associated protein 1) expressed in COR.L23/R cell line in single-dose potentiation assay	ic50	0.0590	uM
(2S)-2-amino-5-[[(2R)-1-(carboxymethylamino)-1-oxo-3-[2-oxo-2-[(2S,4S)-2,4,5,12-tetrahydroxy-7-methoxy-6,11-dioxo-3,4-dihydro-1H-tetracen-2-yl]ethyl]sulfanylpropan-2-yl]amino]-5-oxopentanoic acid	679010: TP_TRANSPORTER: inhibition of LTC4 uptake in membrane vesicles from SR3A cells	ki	0.0600	uM
4-[4-[2-(3,4-difluorophenyl)ethyl]piperazin-1-yl]-N-(pyridin-2-ylmethyl)-6,7,8,9-tetrahydropyrimido[4,5-b]indolizine-10-carboxamide	106552: Inhibitory activity against human transporter MRP1 (Multidrug resistance associated protein 1) expressed in COR.L23/R cell line	ic50	0.0610	uM
6-[4-[2-(3,4-difluorophenyl)ethyl]piperazin-1-yl]-13-methoxy-8-methyl-3,5,8,12-tetrazatricyclo[7.4.0.02,7]trideca-1(9),2(7),3,5,10,12-hexaene	106553: Inhibitory activity against MRP1 (Multidrug resistance associated protein 1) expressed in COR.L23/R cell line in single-dose potentiation assay	ic50	0.0630	uM
4-[4-[2-(3,4-difluorophenyl)ethyl]piperazin-1-yl]-5H-pyrimido[5,4-b]indole-9-carboxamide	106553: Inhibitory activity against MRP1 (Multidrug resistance associated protein 1) expressed in COR.L23/R cell line in single-dose potentiation assay	ic50	0.0650	uM
(2S)-N-[(3S,5R,8R,9R,10R,12R,13R,14R,17S)-12-hydroxy-17-[(2S,5R)-5-(2-hydroxypropan-2-yl)-2-methyloxolan-2-yl]-4,4,8,10,14-pentamethyl-2,3,5,6,7,9,11,12,13,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-yl]pyrrolidine-2-carboxamide	1981530: Inhibition of ABCC1 (unknown origin) overexpressing human KBV cells mediated efflux assessed as adriamycin IC50 using adriamycin as substrate at 10 uM	ic50	0.0660	uM
6-[4-[2-(3,4-difluorophenyl)ethyl]piperazin-1-yl]-8,11-dimethyl-3,5,8,10-tetrazatricyclo[7.4.0.02,7]trideca-1(13),2(7),3,5,9,11-hexaene-13-carboxamide	106553: Inhibitory activity against MRP1 (Multidrug resistance associated protein 1) expressed in COR.L23/R cell line in single-dose potentiation assay	ic50	0.0670	uM
Daunorubicin	679010: TP_TRANSPORTER: inhibition of LTC4 uptake in membrane vesicles from SR3A cells	ki	0.0700	uM
6-methyl-2-[4-[2-[2-[2-[2-[2-[4-(6-methyl-4-oxochromen-2-yl)phenoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]phenyl]chromen-4-one	1414427: Inhibition of MRP1 in human 2008/MRP1 cells assessed as potentiation of doxorubicin-induced cytotoxicity by measuring reduction in cell survival after 5 days by MTS assay	ec50	0.0730	uM
4-[4-[2-(3,4-difluorophenyl)ethyl]piperazin-1-yl]-N-pyridin-3-yl-6,7,8,9-tetrahydropyrimido[4,5-b]indolizine-10-carboxamide	106552: Inhibitory activity against human transporter MRP1 (Multidrug resistance associated protein 1) expressed in COR.L23/R cell line	ic50	0.0760	uM
ethyl 2-[4-[4-[2-(3,4-difluorophenyl)ethyl]piperazin-1-yl]-8-nitropyrimido[5,4-b]indol-5-yl]acetate	106553: Inhibitory activity against MRP1 (Multidrug resistance associated protein 1) expressed in COR.L23/R cell line in single-dose potentiation assay	ic50	0.0780	uM
4-[4-[2-(3,4-difluorophenyl)ethyl]piperazin-1-yl]-8-methoxy-9-nitro-5H-pyrimido[5,4-b]indole	106551: In vitro inhibitory activity against MRP1 (Multidrug resistance associated protein 1) expressed in COR.L23/R cell line in accumulation assay	ic50	0.0780	uM
7-[2-[benzyl-[[1-[2-[2-[4-(4-oxochromen-2-yl)phenoxy]ethoxy]ethyl]triazol-4-yl]methyl]amino]ethoxy]-2-phenylchromen-4-one	1414427: Inhibition of MRP1 in human 2008/MRP1 cells assessed as potentiation of doxorubicin-induced cytotoxicity by measuring reduction in cell survival after 5 days by MTS assay	ec50	0.0780	uM
Verapamil	1981530: Inhibition of ABCC1 (unknown origin) overexpressing human KBV cells mediated efflux assessed as adriamycin IC50 using adriamycin as substrate at 10 uM	ic50	0.0790	uM
11-chloro-6-[4-[2-(3,4-difluorophenyl)ethyl]piperazin-1-yl]-8-methyl-3,5,8,12-tetrazatricyclo[7.4.0.02,7]trideca-1(13),2(7),3,5,9,11-hexaene	106553: Inhibitory activity against MRP1 (Multidrug resistance associated protein 1) expressed in COR.L23/R cell line in single-dose potentiation assay	ic50	0.0870	uM
7-[4-[1-[2-[2-[4-(4-oxochromen-2-yl)phenoxy]ethoxy]ethyl]triazol-4-yl]butoxy]-2-phenylchromen-4-one	1414427: Inhibition of MRP1 in human 2008/MRP1 cells assessed as potentiation of doxorubicin-induced cytotoxicity by measuring reduction in cell survival after 5 days by MTS assay	ec50	0.0870	uM
6-[4-[2-(3,4-difluorophenyl)ethyl]piperazin-1-yl]-8-methyl-3,5,8,13-tetrazatricyclo[7.4.0.02,7]trideca-1(9),2(7),3,5,10,12-hexaene	106553: Inhibitory activity against MRP1 (Multidrug resistance associated protein 1) expressed in COR.L23/R cell line in single-dose potentiation assay	ic50	0.0940	uM
7-[3-[1-[2-[2-[2-[4-(6-fluoro-4-oxochromen-2-yl)phenoxy]ethoxy]ethoxy]ethyl]triazol-4-yl]propoxy]-2-phenylchromen-4-one	1414427: Inhibition of MRP1 in human 2008/MRP1 cells assessed as potentiation of doxorubicin-induced cytotoxicity by measuring reduction in cell survival after 5 days by MTS assay	ec50	0.0950	uM
7-[2-[benzyl-[[1-[2-[2-[2-[4-(4-oxochromen-2-yl)phenoxy]ethoxy]ethoxy]ethyl]triazol-4-yl]methyl]amino]ethoxy]-2-phenylchromen-4-one	1414427: Inhibition of MRP1 in human 2008/MRP1 cells assessed as potentiation of doxorubicin-induced cytotoxicity by measuring reduction in cell survival after 5 days by MTS assay	ec50	0.0990	uM
7-fluoro-2-[4-[3-[1-[2-[2-[2-[4-(6-fluoro-4-oxochromen-2-yl)phenoxy]ethoxy]ethoxy]ethyl]triazol-4-yl]propoxy]phenyl]chromen-4-one	1414427: Inhibition of MRP1 in human 2008/MRP1 cells assessed as potentiation of doxorubicin-induced cytotoxicity by measuring reduction in cell survival after 5 days by MTS assay	ec50	0.1030	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Doxorubicin	increases reaction, decreases reaction, affects reaction, affects activity, increases uptake (+9 more)	33
verlukast	increases export, increases expression, increases activity, increases response to substance, increases abundance (+11 more)	22
Vincristine	decreases response to substance, affects transport, decreases reaction, affects expression, increases transport (+5 more)	19
Glutathione	affects binding, increases activity, decreases degradation, affects cotreatment, decreases response to substance (+15 more)	16
Daunorubicin	affects response to substance, affects export, decreases response to substance, increases export, increases secretion (+4 more)	12
Arsenic Trioxide	increases response to substance, decreases response to substance, decreases uptake, increases secretion, decreases expression (+4 more)	11
Adenosine Triphosphate	affects folding, increases reaction, increases degradation, affects activity, increases transport (+5 more)	11
Etoposide	affects expression, affects export, affects response to substance, decreases response to substance, affects cotreatment (+2 more)	11
Indomethacin	increases response to substance, increases transport, affects export, decreases reaction, decreases response to substance (+6 more)	11
Quercetin	increases activity, increases hydrolysis, affects export, increases expression, decreases response to substance (+10 more)	11
Cisplatin	decreases response to substance, affects cotreatment, increases expression, increases response to substance, decreases expression (+2 more)	9
Probenecid	decreases reaction, increases export, decreases activity, decreases export, affects activity (+2 more)	9
Verapamil	affects activity, decreases reaction, increases export, increases uptake, decreases activity (+4 more)	9
sodium arsenite	decreases response to substance, affects binding, increases reaction, increases abundance, increases expression (+1 more)	8
Leukotriene C4	affects transport, decreases transport, increases uptake, decreases reaction, affects reaction (+4 more)	8
Methotrexate	affects transport, increases transport, decreases response to substance, increases export, decreases expression (+2 more)	7
fluorexon	affects export, increases export, affects activity, decreases reaction, affects transport (+3 more)	6
estradiol-17 beta-glucuronide	increases reaction, affects binding, affects cotreatment, affects reaction, affects transport (+4 more)	6
Epirubicin	increases expression, affects cotreatment, affects response to substance, decreases response to substance, decreases reaction	6
Acetaminophen	increases transport, affects cotreatment, increases activity, increases expression, affects activity	5
Antimony Potassium Tartrate	affects reaction, affects expression, decreases reaction, affects response to substance, decreases response to substance (+1 more)	5
Genistein	affects reaction, increases uptake, decreases activity, increases reaction, affects activity	5
arsenite	increases transport, decreases reaction, decreases abundance, affects cotreatment, affects transport (+1 more)	4
calcein AM	decreases activity, increases export, increases expression, decreases reaction, decreases export (+2 more)	4
Resveratrol	affects cotreatment, decreases expression, increases uptake, increases hydrolysis, increases reaction (+3 more)	4
Acetylcysteine	decreases expression, decreases reaction, increases expression, decreases response to substance, increases reaction	4
Arsenic	affects expression, increases activity, increases expression, affects cotreatment, increases abundance (+1 more)	4
Benzbromarone	decreases reaction, increases export, increases secretion, affects activity	4
Benzo(a)pyrene	increases methylation, affects methylation, increases expression	4
Chlorambucil	affects export, decreases response to substance, increases response to substance, increases reaction	4

ChEMBL screening assays

459 unique, capped per target: 270 binding, 166 functional, 23 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1004849	Binding	Inhibition of human MRP1 in hamster BHK21 cells assessed as increase in calcein-AM accumulation at 30 uM	(R)- and (S)-verapamil differentially modulate the multidrug-resistant protein MRP1. — J Biol Chem
CHEMBL2013262	ADMET	Inhibition of MRP1	Discovery of GS-9451: an acid inhibitor of the hepatitis C virus NS3/4A protease. — Bioorg Med Chem Lett
CHEMBL2075050	Functional	TP_TRANSPORTER: drug resistance in MRP1-expressing NIH/3T3 cells	The multidrug resistance-associated protein 1 transports methoxychlor and protects the seminiferous epithelium from injury. — Toxicol Lett

Cellosaurus cell lines

21 cell lines: 11 cancer cell line, 5 spontaneously immortalized cell line, 5 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_0E38	MV522/MRP	Cancer cell line	Female
CVCL_A5BC	SW1573/S1(MRP)	Cancer cell line	Female
CVCL_B1EG	Abcam A-549 ABCC1 KO	Cancer cell line	Male
CVCL_B1IK	Abcam HeLa ABCC1 KO	Cancer cell line	Female
CVCL_B5ZY	C2BBe1 MRP1 KO	Cancer cell line	Male
CVCL_B8AQ	Abcam HCT 116 ABCC1 KO	Cancer cell line	Male
CVCL_B8S1	Abcam MCF-7 ABCC1 KO	Cancer cell line	Female
CVCL_E1JD	HyCyte Bewo KO-hABCC1	Cancer cell line	Male
CVCL_E5ZG	CHO-K1 MRP1/ABCC1 WT	Spontaneously immortalized cell line	Female
CVCL_E5ZH	CHO-K1 MRP1/ABCC1 Arg1058Gln	Spontaneously immortalized cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00211796	PHASE4	COMPLETED	Divalproex Sodium ER in Adult Autism
NCT00391261	PHASE4	COMPLETED	An Open-label Trial of Metformin for Weight Control of Pediatric Patients on Antipsychotic Medications.
NCT00409747	PHASE4	COMPLETED	Minocycline to Treat Childhood Regressive Autism
NCT00576732	PHASE4	COMPLETED	A Study of the Effectiveness and Safety of Two Doses of Risperidone in the Treatment of Children and Adolescents With Autistic Disorder
NCT00844753	PHASE4	COMPLETED	Atomoxetine, Placebo and Parent Management Training in Autism
NCT01028820	PHASE4	COMPLETED	FMRI Brain Activation of Aripiprazole Treatment in Autism Spectrum Disorders
NCT01098383	PHASE4	UNKNOWN	Treatment With Acetyl-Choline Esterase Inhibitors in Children With Autism Spectrum Disorders
NCT01333865	PHASE4	COMPLETED	A Study of Memantine Hydrochloride (Namenda®) for Cognitive and Behavioral Impairment in Adults With Autism Spectrum Disorders
NCT01337700	PHASE4	COMPLETED	Milnacipran in Autism and the Functional Locus Coeruleus and Noradrenergic Model of Autism
NCT01695200	PHASE4	COMPLETED	Omega-3 Fatty Acids in Autism Spectrum Disorders
NCT02069977	PHASE4	UNKNOWN	Study to Evaluate the Efficacy and Safety of Aripiprazole
NCT02096952	PHASE4	COMPLETED	Methylphenidate ER Liquid Formulation in Adults With ASD and ADHD
NCT02199925	PHASE4	UNKNOWN	An Open-Label Study to Evaluate the Efficacy of High-Dose Gammaplex in Children on the Autism Spectrum
NCT02235467	PHASE4	COMPLETED	Multisite Study: Parental Training Using Video Modelling to Develop Social Skills in Children With Autism
NCT02255565	PHASE4	COMPLETED	Dose Response Effects of Quillivant XR in Children With ADHD and Autism: A Pilot Study
NCT02940574	PHASE4	COMPLETED	Neural and Behavioral Effects of Oxytocin in Autism Spectrum Disorders
NCT03333629	PHASE4	COMPLETED	Promoting Positive Outcomes for Individuals With ASD: Linking Early Detection, Treatment, and Long-term Outcomes
NCT03337646	PHASE4	COMPLETED	Evaluation of the Effect and Safety of Lisdexamfetamine in Children Aged 6-12 With ADHD and Autism
NCT03538431	PHASE4	COMPLETED	Improving Driving in Young People With Autism Spectrum Disorders
NCT03757585	PHASE4	COMPLETED	Natural Treatments for the Management of Emotional Dysregulation in Youth With Non-verbal Learning Disability (NVLD) and/or Autism Spectrum Disorders (ASD)
NCT04903353	PHASE4	COMPLETED	Pragmatic Trial Comparing Weight Gain in Children With Autism Taking Risperidone Versus Aripiprazole
NCT05063656	PHASE4	COMPLETED	Biomarker-Driven Pharmacological Treatment of Adolescents With Autism Spectrum Disorder With Gabapentin
NCT05146245	PHASE4	UNKNOWN	Safety and Pharmacokinetics of Antipsychotics in Children 2: Studying TDM in an RCT
NCT05916339	PHASE4	RECRUITING	AWARE: Management of ADHD in Autism Spectrum Disorder
NCT05954052	PHASE4	TERMINATED	A Study of Glutathione in Children With Autism Spectrum Disorder
NCT06853665	PHASE4	RECRUITING	The TEAM Study - Treatment Efficacy for Autism/Attention Using Mixed Amphetamine
NCT07054697	PHASE4	COMPLETED	Pilot-RCT With Individualized Homeopathic Treatment in the Children With Autism Spectrum Disorder
NCT07161804	PHASE4	COMPLETED	Pilot RCT Using Homeopathic Medicines in ASD
NCT07439042	PHASE4	NOT_YET_RECRUITING	Buspirone for Anxiety in Autistic Youth
NCT00036231	PHASE3	TERMINATED	Synthetic Human Secretin in Children With Autism and Gastrointestinal Dysfunction
NCT00036244	PHASE3	COMPLETED	Synthetic Human Secretin in Children With Autism
NCT00065884	PHASE3	UNKNOWN	Valproate Response in Aggressive Autistic Adolescents
NCT00065962	PHASE3	COMPLETED	Secretin for the Treatment of Autism
NCT00252603	PHASE3	COMPLETED	Galantamine Versus Placebo in Childhood Autism
NCT00346736	PHASE3	COMPLETED	Use of Acupuncture In Children With Autistic Spectrum Disorder
NCT00352248	PHASE3	COMPLETED	Randomized Controlled Trial of Acupuncture Versus Sham Acupuncture in Autistic Spectrum Disorder
NCT00352352	PHASE3	COMPLETED	Use of Acupuncture In Children With Autistic Spectrum Disorder
NCT00355329	PHASE3	COMPLETED	Randomized Control Trial of Using Tongue Acupuncture in Autistic Spectrum Disorder Using PET Scan for Clinical Correlation
NCT00498173	PHASE3	COMPLETED	Effectiveness of Atomoxetine in Treating ADHD Symptoms in Children and Adolescents With Autism
NCT00541346	PHASE3	COMPLETED	A Pilot Study of Daytrana TM in Children With Autism Co-Morbid for Attention Deficit Hyperactivity Disorder (ADHD) Symptoms