Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTSU7ESK)

• DOT Name: Translocator protein (TSPO)
• Synonyms: Mitochondrial benzodiazepine receptor; PKBS; Peripheral-type benzodiazepine receptor; PBR
• Gene Name: TSPO
• UniProt ID: TSPO_HUMAN
• Pfam ID: PF03073
• Sequence:
  MAPPWVPAMGFTLAPSLGCFVGSRFVHGEGLRWYAGLQKPSWHPPHWVLGPVWGTLYSAM
  GYGSYLVWKELGGFTEKAVVPLGLYTGQLALNWAWPPIFFGARQMGWALVDLLLVSGAAA
  ATTVAWYQVSPLAARLLYPYLAWLAFTTTLNYCVWRDNHGWRGGRRLPE
• Function: Can bind protoporphyrin IX and may play a role in the transport of porphyrins and heme. Promotes the transport of cholesterol across mitochondrial membranes and may play a role in lipid metabolism , but its precise physiological role is controversial. It is apparently not required for steroid hormone biosynthesis. Was initially identified as peripheral-type benzodiazepine receptor; can also bind isoquinoline carboxamides.
• Tissue Specificity: Found in many tissue types. Expressed at the highest levels under normal conditions in tissues that synthesize steroids.
• KEGG Pathway:
  Neuroactive ligand-receptor interaction (hsa04080)
  Cholesterol metabolism (hsa04979)
  Human T-cell leukemia virus 1 infection (hsa05166)
• Reactome Pathway: Pregnenolone biosynthesis (R-HSA-196108)

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Diazepam	DM08E9O	Approved	Translocator protein (TSPO) increases the Sedation ADR of Diazepam.	[20]
Alprazolam	DMC7XDN	Approved	Translocator protein (TSPO) increases the Anterograde amnesia ADR of Alprazolam.	[20]

1 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 Translocator protein (TSPO).	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Translocator protein (TSPO).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Translocator protein (TSPO).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Translocator protein (TSPO).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin affects the expression of Translocator protein (TSPO).	[5]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Translocator protein (TSPO).	[6]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Translocator protein (TSPO).	[7]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Translocator protein (TSPO).	[8]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Translocator protein (TSPO).	[5]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Translocator protein (TSPO).	[9]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Translocator protein (TSPO).	[10]
Cytarabine	DMZD5QR	Approved	Cytarabine decreases the expression of Translocator protein (TSPO).	[11]
Menthol	DMG2KW7	Approved	Menthol decreases the expression of Translocator protein (TSPO).	[12]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Translocator protein (TSPO).	[10]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Translocator protein (TSPO).	[14]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of Translocator protein (TSPO).	[16]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Translocator protein (TSPO).	[17]
chloropicrin	DMSGBQA	Investigative	chloropicrin decreases the expression of Translocator protein (TSPO).	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
SSR-180575	DMA0QZH	Phase 2	SSR-180575 affects the binding of Translocator protein (TSPO).	[13]
Emapunil	DM0RXCK	Discontinued in Phase 2	Emapunil affects the binding of Translocator protein (TSPO).	[15]
PK 11195	DMDOZPU	Investigative	PK 11195 affects the binding of Translocator protein (TSPO).	[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] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [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] 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] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [6] Minimal peroxide exposure of neuronal cells induces multifaceted adaptive responses. PLoS One. 2010 Dec 17;5(12):e14352. doi: 10.1371/journal.pone.0014352.
• [7] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [8] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [9] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [10] 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.
• [11] Cytosine arabinoside induces ectoderm and inhibits mesoderm expression in human embryonic stem cells during multilineage differentiation. Br J Pharmacol. 2011 Apr;162(8):1743-56.
• [12] Repurposing L-menthol for systems medicine and cancer therapeutics? L-menthol induces apoptosis through caspase 10 and by suppressing HSP90. OMICS. 2016 Jan;20(1):53-64.
• [13] SSR180575 (7-chloro-N,N,5-trimethyl-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-acetamide), a peripheral benzodiazepine receptor ligand, promotes neuronal survival and repair. J PharmacolExp Ther. 2002 Jun;301(3):1067-78.
• [14] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [15] Synthesis and evaluation of novel carbon-11 labeled oxopurine analogues for positron emission tomography imaging of translocator protein (18 kDa) in peripheral organs. J Med Chem. 2011 Sep 8;54(17):6040-9. doi: 10.1021/jm200516a. Epub 2011 Aug 4.
• [16] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [17] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [18] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.
• [19] Peripheral benzodiazepine receptor ligands induce apoptosis and cell cycle arrest in human hepatocellular carcinoma cells and enhance chemosensitivity to paclitaxel, docetaxel, doxorubicin and the Bcl-2 inhibitor HA14-1. J Hepatol. 2004 Nov;41(5):799-807. doi: 10.1016/j.jhep.2004.07.015.
• [20] ADReCS-Target: target profiles for aiding drug safety research and application. Nucleic Acids Res. 2018 Jan 4;46(D1):D911-D917. doi: 10.1093/nar/gkx899.