Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTGR686L)

• DOT Name: Metal cation symporter ZIP14 (SLC39A14)
• Synonyms: LIV-1 subfamily of ZIP zinc transporter 4; LZT-Hs4; Solute carrier family 39 member 14; Zrt- and Irt-like protein 14; ZIP-14
• Gene Name: SLC39A14
• Related Disease:
  Hypermanganesemia with dystonia 2
  Hyperostosis cranialis interna
• UniProt ID: S39AE_HUMAN
• Pfam ID: PF02535
• Sequence:
  MKLLLLHPAFQSCLLLTLLGLWRTTPEAHASSLGAPAISAASFLQDLIHRYGEGDSLTLQ
  QLKALLNHLDVGVGRGNVTQHVQGHRNLSTCFSSGDLFTAHNFSEQSRIGSSELQEFCPT
  ILQQLDSRACTSENQENEENEQTEEGRPSAVEVWGYGLLCVTVISLCSLLGASVVPFMKK
  TFYKRLLLYFIALAIGTLYSNALFQLIPEAFGFNPLEDYYVSKSAVVFGGFYLFFFTEKI
  LKILLKQKNEHHHGHSHYASESLPSKKDQEEGVMEKLQNGDLDHMIPQHCSSELDGKAPM
  VDEKVIVGSLSVQDLQASQSACYWLKGVRYSDIGTLAWMITLSDGLHNFIDGLAIGASFT
  VSVFQGISTSVAILCEEFPHELGDFVILLNAGMSIQQALFFNFLSACCCYLGLAFGILAG
  SHFSANWIFALAGGMFLYISLADMFPEMNEVCQEDERKGSILIPFIIQNLGLLTGFTIMV
  VLTMYSGQIQIG
• Function: Electroneutral transporter of the plasma membrane mediating the cellular uptake of the divalent metal cations zinc, manganese and iron that are important for tissue homeostasis, metabolism, development and immunity. Functions as an energy-dependent symporter, transporting through the membranes an electroneutral complex composed of a divalent metal cation and two bicarbonate anions. Beside these endogenous cellular substrates, can also import cadmium a non-essential metal which is cytotoxic and carcinogenic. Controls the cellular uptake by the intestinal epithelium of systemic zinc, which is in turn required to maintain tight junctions and the intestinal permeability. Modifies the activity of zinc-dependent phosphodiesterases, thereby indirectly regulating G protein-coupled receptor signaling pathways important for gluconeogenesis and chondrocyte differentiation. Regulates insulin receptor signaling, glucose uptake, glycogen synthesis and gluconeogenesis in hepatocytes through the zinc-dependent intracellular catabolism of insulin. Through zinc cellular uptake also plays a role in the adaptation of cells to endoplasmic reticulum stress. Major manganese transporter of the basolateral membrane of intestinal epithelial cells, it plays a central role in manganese systemic homeostasis through intestinal manganese uptake. Also involved in manganese extracellular uptake by cells of the blood-brain barrier. May also play a role in manganese and zinc homeostasis participating in their elimination from the blood through the hepatobiliary excretion. Also functions in the extracellular uptake of free iron. May also function intracellularly and mediate the transport from endosomes to cytosol of iron endocytosed by transferrin. Plays a role in innate immunity by regulating the expression of cytokines by activated macrophages.
• Tissue Specificity: Ubiquitously expressed, with higher expression in liver, pancreas, fetal liver, thyroid gland, left and right ventricle, right atrium and fetal heart . Weakly expressed in spleen, thymus, and peripheral blood leukocytes . Expressed in liver and in brain by large neurons in the globus pallidus, the insular cortex and the dentate nucleus and to a lower extent in the putamen and the caudate nucleus (at protein level) . Expressed in osteoblasts and giant osteoclast-like cells, but not in osteocytes found osteoblastoma and giant cell tumors (at protein level) . Expressed by microvascular capillary endothelial cells that constitute the blood-brain barrier (at protein level) . Expressed by macrophages .; [Isoform 2]: Widely expressed but not detected in brain, heart, skeletal muscle, placenta and fetal skin.
• KEGG Pathway:
  Ferroptosis (hsa04216)
  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 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hypermanganesemia with dystonia 2	DISGVSB2	Strong	Autosomal recessive	[1]
Hyperostosis cranialis interna	DISYQZKZ	Limited	Autosomal dominant	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Manganese	DMKT129	Investigative	Metal cation symporter ZIP14 (SLC39A14) affects the uptake of Manganese.	[25]

4 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 Metal cation symporter ZIP14 (SLC39A14).	[3]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Metal cation symporter ZIP14 (SLC39A14).	[21]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Metal cation symporter ZIP14 (SLC39A14).	[23]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Metal cation symporter ZIP14 (SLC39A14).	[24]

19 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 Metal cation symporter ZIP14 (SLC39A14).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Metal cation symporter ZIP14 (SLC39A14).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Metal cation symporter ZIP14 (SLC39A14).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Metal cation symporter ZIP14 (SLC39A14).	[7]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Metal cation symporter ZIP14 (SLC39A14).	[8]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Metal cation symporter ZIP14 (SLC39A14).	[9]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Metal cation symporter ZIP14 (SLC39A14).	[10]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Metal cation symporter ZIP14 (SLC39A14).	[11]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Metal cation symporter ZIP14 (SLC39A14).	[12]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Metal cation symporter ZIP14 (SLC39A14).	[13]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Metal cation symporter ZIP14 (SLC39A14).	[14]
Cannabidiol	DM0659E	Approved	Cannabidiol increases the expression of Metal cation symporter ZIP14 (SLC39A14).	[15]
Isotretinoin	DM4QTBN	Approved	Isotretinoin increases the expression of Metal cation symporter ZIP14 (SLC39A14).	[16]
Zidovudine	DM4KI7O	Approved	Zidovudine decreases the expression of Metal cation symporter ZIP14 (SLC39A14).	[17]
Acetic Acid, Glacial	DM4SJ5Y	Approved	Acetic Acid, Glacial increases the expression of Metal cation symporter ZIP14 (SLC39A14).	[18]
Motexafin gadolinium	DMEJKRF	Approved	Motexafin gadolinium increases the expression of Metal cation symporter ZIP14 (SLC39A14).	[18]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Metal cation symporter ZIP14 (SLC39A14).	[19]
Epigallocatechin gallate	DMCGWBJ	Phase 3	Epigallocatechin gallate increases the expression of Metal cation symporter ZIP14 (SLC39A14).	[20]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Metal cation symporter ZIP14 (SLC39A14).	[22]

References

• [1] Mutations in SLC39A14 disrupt manganese homeostasis and cause childhood-onset parkinsonism-dystonia. Nat Commun. 2016 May 27;7:11601. doi: 10.1038/ncomms11601.
• [2] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [3] 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.
• [4] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [5] 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.
• [6] 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.
• [7] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [8] The thioxotriazole copper(II) complex A0 induces endoplasmic reticulum stress and paraptotic death in human cancer cells. J Biol Chem. 2009 Sep 4;284(36):24306-19.
• [9] 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.
• [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] 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.
• [12] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [13] Delta9-tetrahydrocannabinol inhibits cytotrophoblast cell proliferation and modulates gene transcription. Mol Hum Reprod. 2006 May;12(5):321-33. doi: 10.1093/molehr/gal036. Epub 2006 Apr 5.
• [14] 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.
• [15] Cannabidiol induces antioxidant pathways in keratinocytes by targeting BACH1. Redox Biol. 2020 Jan;28:101321. doi: 10.1016/j.redox.2019.101321. Epub 2019 Sep 5.
• [16] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [17] 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.
• [18] Motexafin gadolinium and zinc induce oxidative stress responses and apoptosis in B-cell lymphoma lines. Cancer Res. 2005 Dec 15;65(24):11676-88.
• [19] 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.
• [20] Molecular mechanisms of action of angiopreventive anti-oxidants on endothelial cells: microarray gene expression analyses. Mutat Res. 2005 Dec 11;591(1-2):198-211.
• [21] 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.
• [22] 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.
• [23] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [24] 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.
• [25] Interleukin-6 enhances manganese accumulation in SH-SY5Y cells: implications of the up-regulation of ZIP14 and the down-regulation of ZnT10. Metallomics. 2014 Apr;6(4):944-9. doi: 10.1039/c3mt00362k.