Details of Drug Off-Target (DOT)

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

• DOT Name: Sulfate transporter (SLC26A2)
• Synonyms: Diastrophic dysplasia protein; Solute carrier family 26 member 2
• Gene Name: SLC26A2
• Related Disease:
  Achondrogenesis type IB
  Atelosteogenesis type II
  Diastrophic dysplasia
  Multiple epiphyseal dysplasia
  Multiple epiphyseal dysplasia type 4
• UniProt ID: S26A2_HUMAN
• PDB ID: 7XLM
• Pfam ID: PF01740 ; PF00916
• Sequence:
  MSSESKEQHNVSPRDSAEGNDSYPSGIHLELQRESSTDFKQFETNDQCRPYHRILIERQE
  KSDTNFKEFVIKKLQKNCQCSPAKAKNMILGFLPVLQWLPKYDLKKNILGDVMSGLIVGI
  LLVPQSIAYSLLAGQEPVYGLYTSFFASIIYFLLGTSRHISVGIFGVLCLMIGETVDREL
  QKAGYDNAHSAPSLGMVSNGSTLLNHTSDRICDKSCYAIMVGSTVTFIAGVYQVAMGFFQ
  VGFVSVYLSDALLSGFVTGASFTILTSQAKYLLGLNLPRTNGVGSLITTWIHVFRNIHKT
  NLCDLITSLLCLLVLLPTKELNEHFKSKLKAPIPIELVVVVAATLASHFGKLHENYNSSI
  AGHIPTGFMPPKVPEWNLIPSVAVDAIAISIIGFAITVSLSEMFAKKHGYTVKANQEMYA
  IGFCNIIPSFFHCFTTSAALAKTLVKESTGCHTQLSGVVTALVLLLVLLVIAPLFYSLQK
  SVLGVITIVNLRGALRKFRDLPKMWSISRMDTVIWFVTMLSSALLSTEIGLLVGVCFSIF
  CVILRTQKPKSSLLGLVEESEVFESVSAYKNLQIKPGIKIFRFVAPLYYINKECFKSALY
  KQTVNPILIKVAWKKAAKRKIKEKVVTLGGIQDEMSVQLSHDPLELHTIVIDCSAIQFLD
  TAGIHTLKEVRRDYEAIGIQVLLAQCNPTVRDSLTNGEYCKKEEENLLFYSVYEAMAFAE
  VSKNQKGVCVPNGLSLSSD
• Function: Sulfate transporter which mediates sulfate uptake into chondrocytes in order to maintain adequate sulfation of proteoglycans which is needed for cartilage development. Mediates electroneutral anion exchange of sulfate ions for oxalate ions and of sulfate and oxalate ions for chloride ions. Mediates exchange of sulfate and oxalate ions for hydroxyl ions and of chloride ions for bromide, iodide and nitrate ions. The coupling of sulfate transport to both hydroxyl and chloride ions likely serves to ensure transport at both acidic pH when most sulfate uptake is mediated by sulfate-hydroxide exchange and alkaline pH when most sulfate uptake is mediated by sulfate-chloride exchange. Essential for chondrocyte proliferation, differentiation and cell size expansion.
• Tissue Specificity: Ubiquitously expressed.
• KEGG Pathway: Chemical carcinogenesis - reactive oxygen species (hsa05208)
• Reactome Pathway:
  Defective SLC26A2 causes chondrodysplasias (R-HSA-3560792)
  Multifunctional anion exchangers (R-HSA-427601)
  Transport and synthesis of PAPS (R-HSA-174362)

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Achondrogenesis type IB	DISBI311	Definitive	Autosomal recessive	[1]
Atelosteogenesis type II	DIS903NR	Definitive	Autosomal recessive	[1]
Diastrophic dysplasia	DISNTGP7	Definitive	Autosomal recessive	[1]
Multiple epiphyseal dysplasia	DIS5FZLR	Definitive	Autosomal recessive	[1]
Multiple epiphyseal dysplasia type 4	DIS890QB	Definitive	Autosomal recessive	[2]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Methotrexate	DM2TEOL	Approved	Sulfate transporter (SLC26A2) affects the response to substance of Methotrexate.	[22]

21 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 Sulfate transporter (SLC26A2).	[3]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Sulfate transporter (SLC26A2).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Sulfate transporter (SLC26A2).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Sulfate transporter (SLC26A2).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Sulfate transporter (SLC26A2).	[7]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Sulfate transporter (SLC26A2).	[8]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Sulfate transporter (SLC26A2).	[9]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Sulfate transporter (SLC26A2).	[10]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Sulfate transporter (SLC26A2).	[11]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Sulfate transporter (SLC26A2).	[12]
Fulvestrant	DM0YZC6	Approved	Fulvestrant decreases the expression of Sulfate transporter (SLC26A2).	[13]
Rifampicin	DM5DSFZ	Approved	Rifampicin decreases the expression of Sulfate transporter (SLC26A2).	[14]
Zidovudine	DM4KI7O	Approved	Zidovudine increases the expression of Sulfate transporter (SLC26A2).	[15]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Sulfate transporter (SLC26A2).	[16]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Sulfate transporter (SLC26A2).	[17]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene affects the expression of Sulfate transporter (SLC26A2).	[5]
Afimoxifene	DMFORDT	Phase 2	Afimoxifene decreases the expression of Sulfate transporter (SLC26A2).	[13]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Sulfate transporter (SLC26A2).	[18]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Sulfate transporter (SLC26A2).	[3]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane increases the expression of Sulfate transporter (SLC26A2).	[20]
Nickel chloride	DMI12Y8	Investigative	Nickel chloride decreases the expression of Sulfate transporter (SLC26A2).	[21]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Sulfate transporter (SLC26A2).	[19]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Sulfate transporter (SLC26A2).	[19]

References

• [1] 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.
• [2] Autosomal recessive multiple epiphyseal dysplasia with homozygosity for C653S in the DTDST gene: double-layer patella as a reliable sign. Am J Med Genet A. 2003 Oct 15;122A(3):187-92. doi: 10.1002/ajmg.a.20282.
• [3] 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.
• [4] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [5] Differential modulation of PI3-kinase/Akt pathway during all-trans retinoic acid- and Am80-induced HL-60 cell differentiation revealed by DNA microarray analysis. Biochem Pharmacol. 2004 Dec 1;68(11):2177-86.
• [6] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [7] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [8] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [9] Long-term estrogen exposure promotes carcinogen bioactivation, induces persistent changes in gene expression, and enhances the tumorigenicity of MCF-7 human breast cancer cells. Toxicol Appl Pharmacol. 2009 Nov 1;240(3):355-66.
• [10] 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.
• [11] Progesterone regulation of implantation-related genes: new insights into the role of oestrogen. Cell Mol Life Sci. 2007 Apr;64(7-8):1009-32.
• [12] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [13] Comparative gene expression profiling reveals partially overlapping but distinct genomic actions of different antiestrogens in human breast cancer cells. J Cell Biochem. 2006 Aug 1;98(5):1163-84.
• [14] Rifampin Regulation of Drug Transporters Gene Expression and the Association of MicroRNAs in Human Hepatocytes. Front Pharmacol. 2016 Apr 26;7:111.
• [15] 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.
• [16] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [17] 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.
• [18] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [19] 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.
• [20] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.
• [21] The contact allergen nickel triggers a unique inflammatory and proangiogenic gene expression pattern via activation of NF-kappaB and hypoxia-inducible factor-1alpha. J Immunol. 2007 Mar 1;178(5):3198-207.
• [22] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.