Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT7EG17X)

• DOT Name: Proton-coupled zinc antiporter SLC30A2 (SLC30A2)
• Synonyms: Solute carrier family 30 member 2; Zinc transporter 2; ZnT-2
• Gene Name: SLC30A2
• UniProt ID: ZNT2_HUMAN
• Pfam ID: PF01545
• Sequence:
  MEAKEKQHLLDARPAIRSYTGSLWQEGAGWIPLPRPGLDLQAIELAAQSNHHCHAQKGPD
  SHCDPKKGKAQRQLYVASAICLLFMIGEVVGGYLAHSLAVMTDAAHLLTDFASMLISLFS
  LWMSSRPATKTMNFGWQRAEILGALVSVLSIWVVTGVLVYLAVERLISGDYEIDGGTMLI
  TSGCAVAVNIIMGLTLHQSGHGHSHGTTNQQEENPSVRAAFIHVIGDFMQSMGVLVAAYI
  LYFKPEYKYVDPICTFVFSILVLGTTLTILRDVILVLMEGTPKGVDFTAVRDLLLSVEGV
  EALHSLHIWALTVAQPVLSVHIAIAQNTDAQAVLKTASSRLQGKFHFHTVTIQIEDYSED
  MKDCQACQGPSD
• Function: [Isoform 1]: Electroneutral proton-coupled antiporter concentrating zinc ions into a variety of intracellular organelles including endosomes, zymogen granules and mitochondria. Thereby, plays a crucial role in cellular zinc homeostasis to confer upon cells protection against its potential cytotoxicity. Regulates the zinc concentration of milk, through the transport of zinc ions into secretory vesicles of mammary cells. By concentrating zinc ions into lysosomes participates to lysosomal-mediated cell death during early mammary gland involution ; [Isoform 2]: Electroneutral proton-coupled antiporter mediating the efflux of zinc ions through the plasma membrane.
• Reactome Pathway: Zinc efflux and compartmentalization by the SLC30 family (R-HSA-435368)

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Proton-coupled zinc antiporter SLC30A2 (SLC30A2).	[1]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Proton-coupled zinc antiporter SLC30A2 (SLC30A2).	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Proton-coupled zinc antiporter SLC30A2 (SLC30A2).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Proton-coupled zinc antiporter SLC30A2 (SLC30A2).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Proton-coupled zinc antiporter SLC30A2 (SLC30A2).	[4]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Proton-coupled zinc antiporter SLC30A2 (SLC30A2).	[5]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Proton-coupled zinc antiporter SLC30A2 (SLC30A2).	[6]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Proton-coupled zinc antiporter SLC30A2 (SLC30A2).	[8]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Proton-coupled zinc antiporter SLC30A2 (SLC30A2).	[9]
Paraquat	DMR8O3X	Investigative	Paraquat decreases the expression of Proton-coupled zinc antiporter SLC30A2 (SLC30A2).	[6]
Forskolin	DM6ITNG	Investigative	Forskolin increases the expression of Proton-coupled zinc antiporter SLC30A2 (SLC30A2).	[10]

References

• [1] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [2] Evidence for a role of claudin 2 as a proximal tubular stress responsive paracellular water channel. Toxicol Appl Pharmacol. 2014 Sep 1;279(2):163-72.
• [3] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [4] 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.
• [5] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [6] The MT1G Gene in LUHMES Neurons Is a Sensitive Biomarker of Neurotoxicity. Neurotox Res. 2020 Dec;38(4):967-978. doi: 10.1007/s12640-020-00272-3. Epub 2020 Sep 1.
• [7] 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.
• [8] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [9] 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.
• [10] Induction of zinc transporters by forskolin in human trophoblast BeWo cells. Reprod Toxicol. 2006 Apr;21(3):285-91. doi: 10.1016/j.reprotox.2005.02.006. Epub 2005 Apr 18.