Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT8RV2VY)

• DOT Name: Solute carrier family 40 member 1 (SLC40A1)
• Synonyms: Ferroportin-1; Iron-regulated transporter 1
• Gene Name: SLC40A1
• Related Disease: Hemochromatosis type 4
• UniProt ID: S40A1_HUMAN
• PDB ID: 6W4S; 6WBV; 8BZY; 8C02; 8C03; 8DL6; 8DL7; 8DL8
• Pfam ID: PF06963
• Sequence:
  MTRAGDHNRQRGCCGSLADYLTSAKFLLYLGHSLSTWGDRMWHFAVSVFLVELYGNSLLL
  TAVYGLVVAGSVLVLGAIIGDWVDKNARLKVAQTSLVVQNVSVILCGIILMMVFLHKHEL
  LTMYHGWVLTSCYILIITIANIANLASTATAITIQRDWIVVVAGEDRSKLANMNATIRRI
  DQLTNILAPMAVGQIMTFGSPVIGCGFISGWNLVSMCVEYVLLWKVYQKTPALAVKAGLK
  EEETELKQLNLHKDTEPKPLEGTHLMGVKDSNIHELEHEQEPTCASQMAEPFRTFRDGWV
  SYYNQPVFLAGMGLAFLYMTVLGFDCITTGYAYTQGLSGSILSILMGASAITGIMGTVAF
  TWLRRKCGLVRTGLISGLAQLSCLILCVISVFMPGSPLDLSVSPFEDIRSRFIQGESITP
  TKIPEITTEIYMSNGSNSANIVPETSPESVPIISVSLLFAGVIAARIGLWSFDLTVTQLL
  QENVIESERGIINGVQNSMNYLLDLLHFIMVILAPNPEAFGLLVLISVSFVAMGHIMYFR
  FAQNTLGNKLFACGPDAKEVRKENQANTSVV
• Function: Transports Fe(2+) from the inside of a cell to the outside of the cell, playing a key role for maintaining systemic iron homeostasis. Transports iron from intestinal, splenic, hepatic cells, macrophages and erythrocytes into the blood to provide iron to other tissues. Controls therefore dietary iron uptake, iron recycling by macrophages and erythrocytes, and release of iron stores in hepatocytes. When iron is in excess in serum, circulating HAMP/hepcidin levels increase resulting in a degradation of SLC40A1, thus limiting the iron efflux to plasma.
• Tissue Specificity: Detected in erythrocytes (at protein level) . Expressed in placenta, intestine, muscle and spleen . Highly expressed in mature red blood .
• KEGG Pathway:
  Ferroptosis (hsa04216)
  Mineral absorption (hsa04978)
• Reactome Pathway:
  Defective SLC40A1 causes hemochromatosis 4 (HFE4) (macrophages) (R-HSA-5619049)
  Defective CP causes aceruloplasminemia (ACERULOP) (R-HSA-5619060)
  Defective SLC40A1 causes hemochromatosis 4 (HFE4) (duodenum) (R-HSA-5655799)
  Iron uptake and transport (R-HSA-917937)
  Metal ion SLC transporters (R-HSA-425410)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hemochromatosis type 4	DIS7240J	Definitive	Autosomal recessive	[1]

This DOT Affected the Regulation of Drug Effects of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Manganese	DMKT129	Investigative	Solute carrier family 40 member 1 (SLC40A1) increases the export of Manganese.	[25]

24 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 family 40 member 1 (SLC40A1).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Solute carrier family 40 member 1 (SLC40A1).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Solute carrier family 40 member 1 (SLC40A1).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Solute carrier family 40 member 1 (SLC40A1).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Solute carrier family 40 member 1 (SLC40A1).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Solute carrier family 40 member 1 (SLC40A1).	[7]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Solute carrier family 40 member 1 (SLC40A1).	[8]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Solute carrier family 40 member 1 (SLC40A1).	[9]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Solute carrier family 40 member 1 (SLC40A1).	[10]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Solute carrier family 40 member 1 (SLC40A1).	[11]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Solute carrier family 40 member 1 (SLC40A1).	[12]
Folic acid	DMEMBJC	Approved	Folic acid affects the expression of Solute carrier family 40 member 1 (SLC40A1).	[13]
Azathioprine	DMMZSXQ	Approved	Azathioprine increases the expression of Solute carrier family 40 member 1 (SLC40A1).	[14]
Cytarabine	DMZD5QR	Approved	Cytarabine decreases the expression of Solute carrier family 40 member 1 (SLC40A1).	[15]
Dasatinib	DMJV2EK	Approved	Dasatinib increases the expression of Solute carrier family 40 member 1 (SLC40A1).	[16]
Ethinyl estradiol	DMODJ40	Approved	Ethinyl estradiol affects the expression of Solute carrier family 40 member 1 (SLC40A1).	[17]
Zidovudine	DM4KI7O	Approved	Zidovudine increases the expression of Solute carrier family 40 member 1 (SLC40A1).	[18]
Gallium nitrate	DMF9O6B	Approved	Gallium nitrate decreases the expression of Solute carrier family 40 member 1 (SLC40A1).	[19]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Solute carrier family 40 member 1 (SLC40A1).	[3]
Piperazinyl methyl quinazolinone derivative 2	DM913KS	Patented	Piperazinyl methyl quinazolinone derivative 2 increases the expression of Solute carrier family 40 member 1 (SLC40A1).	[20]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Solute carrier family 40 member 1 (SLC40A1).	[21]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Solute carrier family 40 member 1 (SLC40A1).	[22]
Paraquat	DMR8O3X	Investigative	Paraquat increases the expression of Solute carrier family 40 member 1 (SLC40A1).	[23]
Chlorpyrifos	DMKPUI6	Investigative	Chlorpyrifos increases the expression of Solute carrier family 40 member 1 (SLC40A1).	[24]

References

• [1] A mutation in SLC11A3 is associated with autosomal dominant hemochromatosis. Nat Genet. 2001 Jul;28(3):213-4. doi: 10.1038/90038.
• [2] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [3] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [4] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [5] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [6] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [7] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [8] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [9] Global effects of inorganic arsenic on gene expression profile in human macrophages. Mol Immunol. 2009 Feb;46(4):649-56.
• [10] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [11] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [12] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [13] High folic acid increases cell turnover and lowers differentiation and iron content in human HT29 colon cancer cells. Br J Nutr. 2008 Apr;99(4):703-8.
• [14] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.
• [15] Cytosine arabinoside induces ectoderm and inhibits mesoderm expression in human embryonic stem cells during multilineage differentiation. Br J Pharmacol. 2011 Apr;162(8):1743-56.
• [16] Dasatinib reverses cancer-associated fibroblasts (CAFs) from primary lung carcinomas to a phenotype comparable to that of normal fibroblasts. Mol Cancer. 2010 Jun 27;9:168.
• [17] The genomic response of Ishikawa cells to bisphenol A exposure is dose- and time-dependent. Toxicology. 2010 Apr 11;270(2-3):137-49. doi: 10.1016/j.tox.2010.02.008. Epub 2010 Feb 17.
• [18] Differential gene expression in human hepatocyte cell lines exposed to the antiretroviral agent zidovudine. Arch Toxicol. 2014 Mar;88(3):609-23. doi: 10.1007/s00204-013-1169-3. Epub 2013 Nov 30.
• [19] Role of oxidative stress in the induction of metallothionein-2A and heme oxygenase-1 gene expression by the antineoplastic agent gallium nitrate in human lymphoma cells. Free Radic Biol Med. 2008 Sep 15;45(6):763-72.
• [20] Protective effect of sestrin2 against iron overload and ferroptosis-induced liver injury. Toxicol Appl Pharmacol. 2019 Sep 15;379:114665. doi: 10.1016/j.taap.2019.114665. Epub 2019 Jul 16.
• [21] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [22] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [23] Paraquat-induced ferroptosis suppression via NRF2 expression regulation. Toxicol In Vitro. 2023 Oct;92:105655. doi: 10.1016/j.tiv.2023.105655. Epub 2023 Jul 26.
• [24] Sublethal exposure of organophosphate pesticide chlorpyrifos alters cellular iron metabolism in hepatocytes and macrophages. Int J Mol Med. 2014 Nov;34(5):1395-400. doi: 10.3892/ijmm.2014.1902. Epub 2014 Aug 18.
• [25] The iron transporter ferroportin can also function as a manganese exporter. Biochim Biophys Acta. 2012 Mar;1818(3):651-7. doi: 10.1016/j.bbamem.2011.12.002. Epub 2011 Dec 8.