Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTVILUUN)

• DOT Name: Solute carrier organic anion transporter family member 4C1 (SLCO4C1)
• Synonyms: SLCO4C1; OATP-H; Organic anion transporter M1; OATP-M1; Organic anion transporting polypeptide 4C1; OATP4C1; Solute carrier family 21 member 20
• Gene Name: SLCO4C1
• UniProt ID: SO4C1_HUMAN
• Pfam ID: PF07648 ; PF03137
• Sequence:
  MKSAKGIENLAFVPSSPDILRRLSASPSQIEVSALSSDPQRENSQPQELQKPQEPQKSPE
  PSLPSAPPNVSEEKLRSLSLSEFEEGSYGWRNFHPQCLQRCNTPGGFLLHYCLLAVTQGI
  VVNGLVNISISTVEKRYEMKSSLTGLISSSYDISFCLLSLFVSFFGERGHKPRWLAFAAF
  MIGLGALVFSLPQFFSGEYKLGSLFEDTCVTTRNSTSCTSSTSSLSNYLYVFILGQLLLG
  AGGTPLYTLGTAFLDDSVPTHKSSLYIGTGYAMSILGPAIGYVLGGQLLTIYIDVAMGES
  TDVTEDDPRWLGAWWIGFLLSWIFAWSLIIPFSCFPKHLPGTAEIQAGKTSQAHQSNSNA
  DVKFGKSIKDFPAALKNLMKNAVFMCLVLSTSSEALITTGFATFLPKFIENQFGLTSSFA
  ATLGGAVLIPGAALGQILGGFLVSKFRMTCKNTMKFALFTSGVALTLSFVFMYAKCENEP
  FAGVSESYNGTGELGNLIAPCNANCNCSRSYYYPVCGDGVQYFSPCFAGCSNPVAHRKPK
  VYYNCSCIERKTEITSTAETFGFEAKAGKCETHCAKLPIFLCIFFIVIIFTFMAGTPITV
  SILRCVNHRQRSLALGIQFMVLRLLGTIPGPIIFGFTIDSTCILWDINDCGIKGACWIYD
  NIKMAHMLVAISVTCKVITMFFNGFAIFLYKPPPSATDVSFHKENAVVTNVLAEQDLNKI
  VKEG
• Function: Mediates the transport of organic anions such as steroids (estrone 3-sulfate, chenodeoxycholate, glycocholate) and thyroid hormones (3,3',5-triiodo-L-thyronine (T3), L-thyroxine (T4)), in the kidney. Capable of transporting cAMP and pharmacological substances such as digoxin, ouabain and methotrexate. Transport is independent of sodium, chloride ion, and ATP. Transport activity is stimulated by an acidic extracellular environment due to increased substrate affinity to the transporter. The driving force for this transport activity is currently not known. The role of hydrogencarbonate (HCO3(-), bicarbonate) as the probable counteranion that exchanges for organic anions is still not well defined. Functions as an uptake transporter at the apical membrane, suggesting a role in renal reabsorption. Involved in the renal secretion of the uremic toxin ADMA (N(omega),N(omega)-dimethyl-L-arginine or asymmetrical dimethylarginine), which is associated to cardiovascular events and mortality, and the structurally related amino acids L-arginine and L-homoarginine (a cardioprotective biomarker). Can act bidirectionally, suggesting a dual protective role of this transport protein; exporting L-homoarginine after being synthesized in proximal tubule cells, and mediating uptake of ADMA from the blood into proximal tubule cells where it is degraded by the enzyme dimethylarginine dimethylaminohydrolase 1 (DDAH1). May be involved in sperm maturation by enabling directed movement of organic anions and compounds within or between cells. This ion-transporting process is important to maintain the strict epididymal homeostasis necessary for sperm maturation. May have a role in secretory functions since seminal vesicle epithelial cells are assumed to secrete proteins involved in decapacitation by modifying surface proteins to facilitate the acquisition of the ability to fertilize the egg.
• Tissue Specificity: Predominantly expressed in kidney but also weakly expressed in both fetal liver and kidney.
• Reactome Pathway:
  Transport of organic anions (R-HSA-879518)
  Neutrophil degranulation (R-HSA-6798695)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Regulation of Drug Effects of 3 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
3-iodothyronamine	DM3L0F8	Investigative	Solute carrier organic anion transporter family member 4C1 (SLCO4C1) affects the uptake of 3-iodothyronamine.	[21]
N,N-dimethylarginine	DM0Y8OW	Investigative	Solute carrier organic anion transporter family member 4C1 (SLCO4C1) increases the uptake of N,N-dimethylarginine.	[22]
L-homoarginine	DML83XP	Investigative	Solute carrier organic anion transporter family member 4C1 (SLCO4C1) increases the export of L-homoarginine.	[22]

22 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Solute carrier organic anion transporter family member 4C1 (SLCO4C1).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Solute carrier organic anion transporter family member 4C1 (SLCO4C1).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Solute carrier organic anion transporter family member 4C1 (SLCO4C1).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin affects the expression of Solute carrier organic anion transporter family member 4C1 (SLCO4C1).	[4]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Solute carrier organic anion transporter family member 4C1 (SLCO4C1).	[5]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Solute carrier organic anion transporter family member 4C1 (SLCO4C1).	[6]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Solute carrier organic anion transporter family member 4C1 (SLCO4C1).	[7]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of Solute carrier organic anion transporter family member 4C1 (SLCO4C1).	[8]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Solute carrier organic anion transporter family member 4C1 (SLCO4C1).	[7]
Demecolcine	DMCZQGK	Approved	Demecolcine decreases the expression of Solute carrier organic anion transporter family member 4C1 (SLCO4C1).	[9]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Solute carrier organic anion transporter family member 4C1 (SLCO4C1).	[10]
Azathioprine	DMMZSXQ	Approved	Azathioprine decreases the expression of Solute carrier organic anion transporter family member 4C1 (SLCO4C1).	[11]
Rifampicin	DM5DSFZ	Approved	Rifampicin increases the expression of Solute carrier organic anion transporter family member 4C1 (SLCO4C1).	[12]
Methamphetamine	DMPM4SK	Approved	Methamphetamine increases the expression of Solute carrier organic anion transporter family member 4C1 (SLCO4C1).	[13]
Atenolol	DMNKG1Z	Approved	Atenolol increases the expression of Solute carrier organic anion transporter family member 4C1 (SLCO4C1).	[14]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Solute carrier organic anion transporter family member 4C1 (SLCO4C1).	[7]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of Solute carrier organic anion transporter family member 4C1 (SLCO4C1).	[15]
Belinostat	DM6OC53	Phase 2	Belinostat increases the expression of Solute carrier organic anion transporter family member 4C1 (SLCO4C1).	[7]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Solute carrier organic anion transporter family member 4C1 (SLCO4C1).	[17]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Solute carrier organic anion transporter family member 4C1 (SLCO4C1).	[19]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Solute carrier organic anion transporter family member 4C1 (SLCO4C1).	[9]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane increases the expression of Solute carrier organic anion transporter family member 4C1 (SLCO4C1).	[20]

2 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Solute carrier organic anion transporter family member 4C1 (SLCO4C1).	[16]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Solute carrier organic anion transporter family member 4C1 (SLCO4C1).	[18]

References

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• [13] Methamphetamine alters the normal progression by inducing cell cycle arrest in astrocytes. PLoS One. 2014 Oct 7;9(10):e109603.
• [14] Change in mRNA Expression after Atenolol, a Beta-adrenergic Receptor Antagonist and Association with Pharmacological Response. Arch Drug Inf. 2009 Sep;2(3):41-50. doi: 10.1111/j.1753-5174.2009.00020.x.
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• [18] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
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• [21] Identification and characterization of 3-iodothyronamine intracellular transport. Endocrinology. 2009 Apr;150(4):1991-9.
• [22] The renal transport protein OATP4C1 mediates uptake of the uremic toxin asymmetric dimethylarginine (ADMA) and efflux of cardioprotective L-homoarginine. PLoS One. 2019 Mar 13;14(3):e0213747. doi: 10.1371/journal.pone.0213747. eCollection 2019.