ABCC1 (MRP1) curation notes

UniProt: P33527 (MRP1_HUMAN). HGNC:51. 1531 aa, 17 transmembrane helices, two cytoplasmic
nucleotide-binding domains (NBD1, NBD2). Belongs to the ABC transporter superfamily, ABCC
family, conjugate transporter (TC 3.A.1.208) subfamily. EC 7.6.2.- (7.6.2.2, 7.6.2.3).

Core biochemistry

ABCC1/MRP1 is a primary-active (ATP-hydrolysis-driven) efflux pump for organic anions. It was
cloned from the doxorubicin-selected multidrug-resistant lung-cancer line H69AR as an
overexpressed ABC transporter PMID:1360704.
The prototypical, highest-affinity endogenous substrate is the glutathione S-conjugate
leukotriene C4 (Km ~97 nM) PMID:7961706.
ATP-dependent vesicular transport was demonstrated for LTC4, LTD4, LTE4 and
S-(2,4-dinitrophenyl)glutathione PMID:7961706.

UniProt summarizes the activity as an ATP-dependent transporter that
"hydrolyzes ATP to enable the active transport of organic" anions conjugated with glutathione,
glucuronate or sulfate (file:human/ABCC1/ABCC1-uniprot.txt, CC FUNCTION). Documented catalytic
activities (RHEA, with experimental PubMed evidence) include S-substituted glutathione export
(EC 7.6.2.3, RHEA:19121), LTC4/LTD4/LTE4, glutathione and glutathione disulfide (GSH/GSSG),
estradiol-17-glucuronide, bilirubin mono/bis-glucuronides, taurolithocholate-3-sulfate,
prostaglandin A2-glutathione diastereomers, 2'3'-cGAMP, sphingosine-1-phosphate, daunorubicin
and vincristine.

Substrate breadth / physiological substrates
[PMID:9426231 "The human multidrug resistance protein MRP1 mediates transport of organic" substrates conjugated to glutathione, glucuronide, or sulfate]:
glutathione-, glucuronide- and sulfate-conjugates. Basolateral export of GSH-prostaglandin A
conjugates shown in polarized MDCKII cells, consistent with
PMID:9426231.

Multidrug resistance (drug efflux)

MRP1 confers resistance to a structurally diverse range of drugs. In transfected HEK cells,
[PMID:9281595 "human MRP has also been shown to be a primary active transporter of a" structurally diverse range of organic anionic conjugates];
mouse and human orthologs
[PMID:9281595 "mrp and MRP conferred similar drug resistance profiles, with the" exception that only MRP conferred resistance to the anthracyclines tested].
Many unmodified drugs (vincristine) are co-transported only in the presence of GSH. EC 7.6.2.2
(ABC-type xenobiotic transporter).

Additional (physiologically important but secondary) substrates

• Glutathione / GSSG export: main pathway for GSH release from astrocytes; upregulated by
  monomeric amyloid-beta PMID:26200696,
  [PMID:26200696 "cortical ABCC1 was significantly increased in temporal register with the surge of" Abeta levels].
  UniProt: MRP1 can "export both GSH and its oxidized form GSSG in a protective mechanism"
  "that limits cellular damage especially during oxidative stress" (CC FUNCTION). → redox
  homeostasis / cytoprotection.
• Sphingosine-1-phosphate (S1P) export from mast cells, independent of degranulation
  PMID:17050692,
  MK571-sensitive; siRNA knockdown reduced surface expression and S1P export; S1P transport
  PMID:17050692.
• 2'3'-cGAMP export: direct ATP-dependent exporter limiting cGAS-STING signaling
  PMID:36070769,
  PMID:36070769. (Note: source
  contains the typo "identifed".)
• Cobalamin (vitamin B12) export: proposed cellular cobalamin exporter (Beedholm-Ebsen 2010,
  the paper commented on in PMID:21511966); reviewed in PMID:22547309 as part of the B12
  trafficking pathway; modelled by Reactome (RCbl export). Treated here as a documented but
  non-core / peripheral substrate; primary transport assays are not in the local cache.

Localization

Multi-pass plasma-membrane protein (extracytosolic N-terminus). In polarized epithelia MRP1 is
predominantly basolateral:
- Sertoli cells (blood-testis barrier): PMID:24130369 (IDA, full text, rat/macaque/human).
- Choroid plexus / blood-CSF barrier: PMID:25986174; functional efflux shown ([PMID:25986174 "Functionality of ABCC1, ABCC4, ABCB1" and ABCG2 could be shown in uptake assays]).
- Rat BBB: PMID:18619525 (i.e. basal/abluminal), and basal-lateral in choroid plexus.
- Retinal pigment epithelium: present on both surfaces PMID:31791063 (apical + basolateral + lateral IDA).
- Membrane/plasma-membrane proteomics: NK-cell membrane proteome (HDA, PMID:19946888), hCMEC/D3 (PMID:23137377), RPE plasma membranes (PMID:28112518).
- DFNA77 hearing-loss variant p.Asn590Ser mislocalizes; PMID:31273342.

Over-annotations / context terms judged non-core or over-annotated:
- extracellular exosome (HDA, PMID:20458337): single large exosome proteome; non-core.
- cell junction (immunofluorescence GO_REF:0000052): likely lateral-membrane staining read as
junction; MRP1 is not a junction protein → over-annotation.
- sphingolipid biosynthetic process (Reactome TAS): MRP1 exports the end-product S1P, it does
not perform a biosynthetic step → over-annotation (participation test fails).
- heme catabolic process (Reactome TAS): MRP1 exports bilirubin-glucuronide catabolites
(elimination step); kept non-core.

Disease

Autosomal dominant non-syndromic hearing loss DFNA77 (MIM:618915); variant p.Asn590Ser causes
unstable mRNA and decreased efflux capacity PMID:31273342.

Review decisions summary

Core functions (synthesized): (1) ATP-dependent export of glutathione S-conjugates / LTC4 /
organic anions (GO:0015431); (2) ATP-dependent drug/xenobiotic efflux → multidrug resistance
(GO:0008559); (3) GSH/GSSG export → redox homeostasis (GO:0034634); (4) 2'3'-cGAMP export →
STING regulation (GO:0140359, substrate cGAMP); (5) S1P export → mast-cell signaling
(GO:0034040). Localization: basolateral plasma membrane (GO:0016323).

Generic CC/MF term convention (batch-2 review, 2026-11-11)

Applied consistently across ABCA8/ABCC1/ABCC3/ABCC4: GO:0016020 membrane -> MODIFY to GO:0005886 plasma membrane (paradigm MODIFY case); GO:0022857 transmembrane transporter activity -> TOO_GENERAL (entailed by the specific accepted transporter activities); GO:0005886 plasma membrane -> ACCEPT (the generic PM term is informative, and apical/basolateral sidedness is carried by the gene's own GO:0016324/GO:0016323 rows, not by blanket-MODIFYing the PM parent to a sub-domain).
This gene already conformed (GO:0005886 ACCEPT; GO:0016020 MODIFY->GO:0005886; GO:0022857 TOO_GENERAL); no change needed here.