Details of Drug Off-Target (DOT)

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

• DOT Name: Zinc transporter ZIP9 (SLC39A9)
• Synonyms: Solute carrier family 39 member 9; Zrt- and Irt-like protein 9; ZIP-9
• Gene Name: SLC39A9
• UniProt ID: S39A9_HUMAN
• Pfam ID: PF02535
• Sequence:
  MDDFISISLLSLAMLVGCYVAGIIPLAVNFSEERLKLVTVLGAGLLCGTALAVIVPEGVH
  ALYEDILEGKHHQASETHNVIASDKAAEKSVVHEHEHSHDHTQLHAYIGVSLVLGFVFML
  LVDQIGNSHVHSTDDPEAARSSNSKITTTLGLVVHAAADGVALGAAASTSQTSVQLIVFV
  AIMLHKAPAAFGLVSFLMHAGLERNRIRKHLLVFALAAPVMSMVTYLGLSKSSKEALSEV
  NATGVAMLFSAGTFLYVATVHVLPEVGGIGHSHKPDATGGRGLSRLEVAALVLGCLIPLI
  LSVGHQH
• Function: Transports zinc ions across cell and organelle membranes into the cytoplasm and regulates intracellular zinc homeostasis. Participates in the zinc ions efflux out of the secretory compartments. Regulates intracellular zinc level, resulting in the enhancement of AKT1 and MAPK3/MAPK1 (Erk1/2) phosphorylation in response to the BCR activation. Also functions as a membrane androgen receptor that mediates, through a G protein, the non-classical androgen signaling pathway, characterized by the activation of MAPK3/MAPK1 (Erk1/2) and transcription factors CREB1 or ATF1. This pathway contributes to CLDN1 and CLDN5 expression and tight junction formation between adjacent Sertoli cells. Mediates androgen-induced vascular endothelial cell proliferation through activation of an inhibitory G protein leading to the AKT1 and MAPK3/MAPK1 (Erk1/2) activation which in turn modulate inhibition (phosphorylation) of GSK3B and CCND1 transcription. Moreover, has dual functions as a membrane-bound androgen receptor and as an androgen-dependent zinc transporter both of which are mediated through an inhibitory G protein (Gi) that mediates both MAP kinase and zinc signaling leading to the androgen-dependent apoptotic process.
• Tissue Specificity: Highly expressed in pancreas, testis, and pituitary and moderately in the kidney, liver, uterus, heart, prostate, and brain, whereas expression is lower in the ovary and colon.
• KEGG Pathway:
  Alzheimer disease (hsa05010)
  Parkinson disease (hsa05012)

Molecular Interaction Atlas (MIA) of This DOT

11 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 Zinc transporter ZIP9 (SLC39A9).	[1]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Zinc transporter ZIP9 (SLC39A9).	[2]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Zinc transporter ZIP9 (SLC39A9).	[4]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Zinc transporter ZIP9 (SLC39A9).	[5]
Zidovudine	DM4KI7O	Approved	Zidovudine increases the expression of Zinc transporter ZIP9 (SLC39A9).	[7]
Acetic Acid, Glacial	DM4SJ5Y	Approved	Acetic Acid, Glacial increases the expression of Zinc transporter ZIP9 (SLC39A9).	[8]
Motexafin gadolinium	DMEJKRF	Approved	Motexafin gadolinium increases the expression of Zinc transporter ZIP9 (SLC39A9).	[8]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Zinc transporter ZIP9 (SLC39A9).	[9]
PMID28870136-Compound-48	DMPIM9L	Patented	PMID28870136-Compound-48 increases the expression of Zinc transporter ZIP9 (SLC39A9).	[10]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Zinc transporter ZIP9 (SLC39A9).	[11]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of Zinc transporter ZIP9 (SLC39A9).	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Zinc transporter ZIP9 (SLC39A9).	[3]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Testosterone	DM7HUNW	Approved	Testosterone affects the binding of Zinc transporter ZIP9 (SLC39A9).	[6]

References

• [1] The neuroprotective action of the mood stabilizing drugs lithium chloride and sodium valproate is mediated through the up-regulation of the homeodomain protein Six1. Toxicol Appl Pharmacol. 2009 Feb 15;235(1):124-34.
• [2] 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.
• [3] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [4] 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.
• [5] 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.
• [6] Novel mechanism of endocrine disruption by fungicides through binding to the membrane androgen receptor, ZIP9 (SLC39A9), and antagonizing rapid testosterone induction of the intrinsic apoptotic pathway. Steroids. 2019 Sep;149:108415. doi: 10.1016/j.steroids.2019.05.007. Epub 2019 May 30.
• [7] 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.
• [8] Motexafin gadolinium and zinc induce oxidative stress responses and apoptosis in B-cell lymphoma lines. Cancer Res. 2005 Dec 15;65(24):11676-88.
• [9] 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.
• [10] Oxidative stress modulates theophylline effects on steroid responsiveness. Biochem Biophys Res Commun. 2008 Dec 19;377(3):797-802.
• [11] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [12] Intracellular zinc stores protect the intestinal epithelium from Ochratoxin A toxicity. Toxicol In Vitro. 2009 Dec;23(8):1516-21.