Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT4QBRK3)

• DOT Name: Solute carrier family 41 member 1 (SLC41A1)
• Gene Name: SLC41A1
• Related Disease:
  Nephronophthisis-like nephropathy 2
  Nephropathy
• UniProt ID: S41A1_HUMAN
• Pfam ID: PF01769
• Sequence:
  MSSKPEPKDVHQLNGTGPSASPCSSDGPGREPLAGTSEFLGPDGAGVEVVIESRANAKGV
  REEDALLENGSQSNESDDVSTDRGPAPPSPLKETSFSIGLQVLFPFLLAGFGTVAAGMVL
  DIVQHWEVFQKVTEVFILVPALLGLKGNLEMTLASRLSTAANIGHMDTPKELWRMITGNM
  ALIQVQATVVGFLASIAAVVFGWIPDGHFSIPHAFLLCASSVATAFIASLVLGMIMIGVI
  IGSRKIGINPDNVATPIAASLGDLITLALLSGISWGLYLELNHWRYIYPLVCAFFVALLP
  VWVVLARRSPATREVLYSGWEPVIIAMAISSVGGLILDKTVSDPNFAGMAVFTPVINGVG
  GNLVAVQASRISTFLHMNGMPGENSEQAPRRCPSPCTTFFSPDVNSRSARVLFLLVVPGH
  LVFLYTISCMQGGHTTLTLIFIIFYMTAALLQVLILLYIADWMVHWMWGRGLDPDNFSIP
  YLTALGDLLGTGLLALSFHVLWLIGDRDTDVGD
• Function: Na(+)/Mg(2+) ion exchanger that acts as a predominant Mg(2+) efflux system at the plasma membrane. Transporter activity is driven by the inwardly directed electrochemical gradient for Na(+) ions, thus directly depends on the extracellular Na(+) ion concentration set by Na(+)/K(+) pump. Generates circadian cellular Mg(2+) fluxes that feed back to regulate clock-controlled gene expression and metabolism and facilitate higher energetic demands during the day. Has a role in regulating the activity of ATP-dependent enzymes, including those operating in Krebs cycle and the electron transport chain.
• Tissue Specificity: Highest expression levels in heart and testis, slightly less in skeletal muscles, prostate, adrenal gland and thyroid, and weakest in the hematopoietic tissues bones marrow, lymph node, thymus and spleen. In the kidney, it is expressed in the distal convoluted tubules, macula densa, and thick ascending limb tubular segments of the nephrons .
• Reactome Pathway: Metal ion SLC transporters (R-HSA-425410)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Nephronophthisis-like nephropathy 2	DIS96VS8	Limited	Unknown	[1]
Nephropathy	DISXWP4P	Limited	Autosomal recessive	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Solute carrier family 41 member 1 (SLC41A1).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Solute carrier family 41 member 1 (SLC41A1).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Solute carrier family 41 member 1 (SLC41A1).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Solute carrier family 41 member 1 (SLC41A1).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Solute carrier family 41 member 1 (SLC41A1).	[7]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Solute carrier family 41 member 1 (SLC41A1).	[8]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Solute carrier family 41 member 1 (SLC41A1).	[9]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Solute carrier family 41 member 1 (SLC41A1).	[10]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Solute carrier family 41 member 1 (SLC41A1).	[10]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Solute carrier family 41 member 1 (SLC41A1).	[11]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Solute carrier family 41 member 1 (SLC41A1).	[12]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Solute carrier family 41 member 1 (SLC41A1).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Solute carrier family 41 member 1 (SLC41A1).	[15]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Solute carrier family 41 member 1 (SLC41A1).	[16]

1 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 family 41 member 1 (SLC41A1).	[13]

References

• [1] Mutation of the Mg2+ transporter SLC41A1 results in a nephronophthisis-like phenotype. J Am Soc Nephrol. 2013 May;24(6):967-77. doi: 10.1681/ASN.2012101034. Epub 2013 May 9.
• [2] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [3] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [4] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [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] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [8] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [9] 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.
• [10] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [11] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [12] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [13] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [14] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [15] 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.
• [16] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.