Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT6C6MNV)

• DOT Name: Metal cation symporter ZIP8 (SLC39A8)
• Synonyms: BCG-induced integral membrane protein in monocyte clone 103 protein; LIV-1 subfamily of ZIP zinc transporter 6; LZT-Hs6; Solute carrier family 39 member 8; Zrt- and Irt-like protein 8; ZIP-8
• Gene Name: SLC39A8
• Related Disease:
  SLC39A8-CDG
  Leigh syndrome
• UniProt ID: S39A8_HUMAN
• Pfam ID: PF02535
• Sequence:
  MAPGRAVAGLLLLAAAGLGGVAEGPGLAFSEDVLSVFGANLSLSAAQLQHLLEQMGAASR
  VGVPEPGQLHFNQCLTAEEIFSLHGFSNATQITSSKFSVICPAVLQQLNFHPCEDRPKHK
  TRPSHSEVWGYGFLSVTIINLASLLGLILTPLIKKSYFPKILTFFVGLAIGTLFSNAIFQ
  LIPEAFGFDPKVDSYVEKAVAVFGGFYLLFFFERMLKMLLKTYGQNGHTHFGNDNFGPQE
  KTHQPKALPAINGVTCYANPAVTEANGHIHFDNVSVVSLQDGKKEPSSCTCLKGPKLSEI
  GTIAWMITLCDALHNFIDGLAIGASCTLSLLQGLSTSIAILCEEFPHELGDFVILLNAGM
  STRQALLFNFLSACSCYVGLAFGILVGNNFAPNIIFALAGGMFLYISLADMFPEMNDMLR
  EKVTGRKTDFTFFMIQNAGMLTGFTAILLITLYAGEIELE
• Function: Electroneutral divalent metal cation:bicarbonate symporter of the plasma membrane mediating the cellular uptake of zinc and manganese, two divalent metal cations important for development, tissue homeostasis and immunity. Transports an electroneutral complex composed of a divalent metal cation and two bicarbonate anions or alternatively a bicarbonate and a selenite anion. Thereby, it also contributes to the cellular uptake of selenium, an essential trace metal and micronutrient. Also imports cadmium a non-essential metal which is cytotoxic and carcinogenic. May also transport iron and cobalt through membranes. Through zinc import, indirectly regulates the metal-dependent transcription factor MTF1 and the expression of some metalloproteases involved in cartilage catabolism and also probably heart development. Also indirectly regulates the expression of proteins involved in cell morphology and cytoskeleton organization. Indirectly controls innate immune function and inflammatory response by regulating zinc cellular uptake which in turn modulates the expression of genes specific of these processes. Protects, for instance, cells from injury and death at the onset of inflammation. By regulating zinc influx into monocytes also directly modulates their adhesion to endothelial cells and arteries. Reclaims manganese from the bile at the apical membrane of hepatocytes, thereby regulating the activity of the manganese-dependent enzymes through the systemic levels of the nutrient. Also participates in manganese reabsorption in the proximal tubule of the kidney. By mediating the extracellular uptake of manganese by cells of the blood-brain barrier, may also play a role in the transport of the micronutrient to the brain. With manganese cellular uptake also participates in mitochondrial proper function. Finally, also probably functions intracellularly, translocating zinc from lysosome to cytosol to indirectly enhance the expression of specific genes during TCR-mediated T cell activation.
• Tissue Specificity: Ubiquitously expressed . Expressed in thymus, placenta, lung, liver, pancreas, salivary gland and, to a lower extent, in spleen, testis, ovary, small intestine, colon, leukocyte, heart. Highest expression is observed in pancreas . Expressed by macrophages (at protein level) . Expressed by microvascular capillary endothelial cells that constitute the blood-brain barrier (at protein level) .
• 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
SLC39A8-CDG	DISU46FI	Strong	Autosomal recessive	[1]
Leigh syndrome	DISWQU45	Limited	Autosomal recessive	[2]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Metal cation symporter ZIP8 (SLC39A8) affects the response to substance of Cisplatin.	[22]
Topotecan	DMP6G8T	Approved	Metal cation symporter ZIP8 (SLC39A8) affects the response to substance of Topotecan.	[23]

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 ZIP8 (SLC39A8) affects the transport of Manganese.	[24]

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 Metal cation symporter ZIP8 (SLC39A8).	[3]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Metal cation symporter ZIP8 (SLC39A8).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Metal cation symporter ZIP8 (SLC39A8).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Metal cation symporter ZIP8 (SLC39A8).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Metal cation symporter ZIP8 (SLC39A8).	[7]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Metal cation symporter ZIP8 (SLC39A8).	[8]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Metal cation symporter ZIP8 (SLC39A8).	[9]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Metal cation symporter ZIP8 (SLC39A8).	[10]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Metal cation symporter ZIP8 (SLC39A8).	[11]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Metal cation symporter ZIP8 (SLC39A8).	[12]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Metal cation symporter ZIP8 (SLC39A8).	[13]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Metal cation symporter ZIP8 (SLC39A8).	[10]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Metal cation symporter ZIP8 (SLC39A8).	[14]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Metal cation symporter ZIP8 (SLC39A8).	[8]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Metal cation symporter ZIP8 (SLC39A8).	[16]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Metal cation symporter ZIP8 (SLC39A8).	[17]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Metal cation symporter ZIP8 (SLC39A8).	[8]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Metal cation symporter ZIP8 (SLC39A8).	[18]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Metal cation symporter ZIP8 (SLC39A8).	[19]
QUERCITRIN	DM1DH96	Investigative	QUERCITRIN decreases the expression of Metal cation symporter ZIP8 (SLC39A8).	[20]
BAY11-7082	DMQNOFA	Investigative	BAY11-7082 decreases the expression of Metal cation symporter ZIP8 (SLC39A8).	[21]

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 affects the methylation of Metal cation symporter ZIP8 (SLC39A8).	[15]

References

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• [12] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
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• [14] 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.
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• [21] Cadmium-mediated toxicity of lung epithelia is enhanced through NF-B-mediated transcriptional activation of the human zinc transporter ZIP8. Am J Physiol Lung Cell Mol Physiol. 2012 May 1;302(9):L909-18. doi: 10.1152/ajplung.00351.2011. Epub 2012 Feb 17.
• [22] Role of ZIP8 in regulation of cisplatin sensitivity through Bcl-2. Toxicol Appl Pharmacol. 2019 Jan 1;362:52-58. doi: 10.1016/j.taap.2018.10.016. Epub 2018 Oct 17.
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• [24] Genome-wide association study of toxic metals and trace elements reveals novel associations. Hum Mol Genet. 2015 Aug 15;24(16):4739-45. doi: 10.1093/hmg/ddv190. Epub 2015 May 29.