Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT04411Q)

• DOT Name: Zinc transporter ZIP10 (SLC39A10)
• Synonyms: Solute carrier family 39 member 10; Zrt- and Irt-like protein 10; ZIP-10
• Gene Name: SLC39A10
• UniProt ID: S39AA_HUMAN
• Pfam ID: PF02535
• Sequence:
  MKVHMHTKFCLICLLTFIFHHCNHCHEEHDHGPEALHRQHRGMTELEPSKFSKQAAENEK
  KYYIEKLFERYGENGRLSFFGLEKLLTNLGLGERKVVEINHEDLGHDHVSHLDILAVQEG
  KHFHSHNHQHSHNHLNSENQTVTSVSTKRNHKCDPEKETVEVSVKSDDKHMHDHNHRLRH
  HHRLHHHLDHNNTHHFHNDSITPSERGEPSNEPSTETNKTQEQSDVKLPKGKRKKKGRKS
  NENSEVITPGFPPNHDQGEQYEHNRVHKPDRVHNPGHSHVHLPERNGHDPGRGHQDLDPD
  NEGELRHTRKREAPHVKNNAIISLRKDLNEDDHHHECLNVTQLLKYYGHGANSPISTDLF
  TYLCPALLYQIDSRLCIEHFDKLLVEDINKDKNLVPEDEANIGASAWICGIISITVISLL
  SLLGVILVPIINQGCFKFLLTFLVALAVGTMSGDALLHLLPHSQGGHDHSHQHAHGHGHS
  HGHESNKFLEEYDAVLKGLVALGGIYLLFIIEHCIRMFKHYKQQRGKQKWFMKQNTEEST
  IGRKLSDHKLNNTPDSDWLQLKPLAGTDDSVVSEDRLNETELTDLEGQQESPPKNYLCIE
  EEKIIDHSHSDGLHTIHEHDLHAAAHNHHGENKTVLRKHNHQWHHKHSHHSHGPCHSGSD
  LKETGIANIAWMVIMGDGIHNFSDGLAIGAAFSAGLTGGISTSIAVFCHELPHELGDFAV
  LLKAGMTVKQAIVYNLLSAMMAYIGMLIGTAVGQYANNITLWIFAVTAGMFLYVALVDML
  PEMLHGDGDNEEHGFCPVGQFILQNLGLLFGFAIMLVIALYEDKIVFDIQF
• Function: Zinc-influx transporter. When associated with SLC39A6, the heterodimer formed by SLC39A10 and SLC39A6 mediates cellular zinc uptake to trigger cells to undergo epithelial-to-mesenchymal transition (EMT). SLC39A10-SLC39A6 heterodimers play also an essentiel role in initiating mitosis by importing zinc into cells to initiate a pathway resulting in the onset of mitosis. Plays an important for both mature B-cell maintenance and humoral immune responses. When associated with SLC39A10, the heterodimer controls NCAM1 phosphorylation and integration into focal adhesion complexes during EMT.
• KEGG Pathway:
  Alzheimer disease (hsa05010)
  Parkinson disease (hsa05012)
• Reactome Pathway: Zinc influx into cells by the SLC39 gene family (R-HSA-442380)

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 decreases the methylation of Zinc transporter ZIP10 (SLC39A10).	[1]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Zinc transporter ZIP10 (SLC39A10).	[20]

21 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 Zinc transporter ZIP10 (SLC39A10).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Zinc transporter ZIP10 (SLC39A10).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Zinc transporter ZIP10 (SLC39A10).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Zinc transporter ZIP10 (SLC39A10).	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Zinc transporter ZIP10 (SLC39A10).	[6]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Zinc transporter ZIP10 (SLC39A10).	[2]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Zinc transporter ZIP10 (SLC39A10).	[7]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Zinc transporter ZIP10 (SLC39A10).	[8]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Zinc transporter ZIP10 (SLC39A10).	[9]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Zinc transporter ZIP10 (SLC39A10).	[10]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Zinc transporter ZIP10 (SLC39A10).	[11]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Zinc transporter ZIP10 (SLC39A10).	[12]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Zinc transporter ZIP10 (SLC39A10).	[13]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of Zinc transporter ZIP10 (SLC39A10).	[14]
Zidovudine	DM4KI7O	Approved	Zidovudine decreases the expression of Zinc transporter ZIP10 (SLC39A10).	[15]
Acetic Acid, Glacial	DM4SJ5Y	Approved	Acetic Acid, Glacial affects the expression of Zinc transporter ZIP10 (SLC39A10).	[16]
Motexafin gadolinium	DMEJKRF	Approved	Motexafin gadolinium affects the expression of Zinc transporter ZIP10 (SLC39A10).	[16]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Zinc transporter ZIP10 (SLC39A10).	[17]
GSK2110183	DMZHB37	Phase 2	GSK2110183 decreases the expression of Zinc transporter ZIP10 (SLC39A10).	[18]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Zinc transporter ZIP10 (SLC39A10).	[2]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Zinc transporter ZIP10 (SLC39A10).	[19]

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] 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.
• [3] 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.
• [4] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [5] 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.
• [6] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [7] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [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] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [10] Gene expression profile induced by arsenic trioxide in chronic lymphocytic leukemia cells reveals a central role for heme oxygenase-1 in apoptosis and regulation of matrix metalloproteinase-9. Oncotarget. 2016 Dec 13;7(50):83359-83377.
• [11] 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.
• [12] Cellular zinc homeostasis is a regulator in monocyte differentiation of HL-60 cells by 1 alpha,25-dihydroxyvitamin D3. J Leukoc Biol. 2010 May;87(5):833-44. doi: 10.1189/jlb.0409241. Epub 2010 Jan 20.
• [13] 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.
• [14] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [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] Motexafin gadolinium and zinc induce oxidative stress responses and apoptosis in B-cell lymphoma lines. Cancer Res. 2005 Dec 15;65(24):11676-88.
• [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] Novel ATP-competitive Akt inhibitor afuresertib suppresses the proliferation of malignant pleural mesothelioma cells. Cancer Med. 2017 Nov;6(11):2646-2659. doi: 10.1002/cam4.1179. Epub 2017 Sep 27.
• [19] 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.
• [20] 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.