Details of Drug Off-Target (DOT)

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

• DOT Name: Reticulon-4-interacting protein 1, mitochondrial (RTN4IP1)
• Synonyms: NOGO-interacting mitochondrial protein
• Gene Name: RTN4IP1
• Related Disease:
  Optic atrophy 10 with or without ataxia, intellectual disability, and seizures
  Advanced cancer
  Neoplasm
  Thyroid cancer
  Thyroid gland carcinoma
  Thyroid gland papillary carcinoma
  Thyroid tumor
  Obsolete autosomal recessive optic atrophy
  Optic nerve disorder
• UniProt ID: RT4I1_HUMAN
• PDB ID: 2VN8
• Pfam ID: PF08240 ; PF13602
• Sequence:
  MEFLKTCVLRRNACTAVCFWRSKVVQKPSVRRISTTSPRSTVMPAWVIDKYGKNEVLRFT
  QNMMMPIIHYPNEVIVKVHAASVNPIDVNMRSGYGATALNMKRDPLHVKIKGEEFPLTLG
  RDVSGVVMECGLDVKYFKPGDEVWAAVPPWKQGTLSEFVVVSGNEVSHKPKSLTHTQAAS
  LPYVALTAWSAINKVGGLNDKNCTGKRVLILGASGGVGTFAIQVMKAWDAHVTAVCSQDA
  SELVRKLGADDVIDYKSGSVEEQLKSLKPFDFILDNVGGSTETWAPDFLKKWSGATYVTL
  VTPFLLNMDRLGIADGMLQTGVTVGSKALKHFWKGVHYRWAFFMASGPCLDDIAELVDAG
  KIRPVIEQTFPFSKVPEAFLKVERGHARGKTVINVV
• Function: Plays a role in the regulation of retinal ganglion cell (RGC) neurite outgrowth, and hence in the development of the inner retina and optic nerve. Appears to be a potent inhibitor of regeneration following spinal cord injury.
• Tissue Specificity: Widely expressed in mitochondria-enriched tissues. Found in heart, muscle, kidney, liver, brain and placenta.

Molecular Interaction Atlas (MIA) of This DOT

9 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Optic atrophy 10 with or without ataxia, intellectual disability, and seizures	DIS5V4FM	Definitive	Autosomal recessive	[1]
Advanced cancer	DISAT1Z9	moderate	Altered Expression	[2]
Neoplasm	DISZKGEW	moderate	Altered Expression	[2]
Thyroid cancer	DIS3VLDH	moderate	Altered Expression	[2]
Thyroid gland carcinoma	DISMNGZ0	moderate	Altered Expression	[2]
Thyroid gland papillary carcinoma	DIS48YMM	moderate	Altered Expression	[2]
Thyroid tumor	DISLVKMD	moderate	Altered Expression	[2]
Obsolete autosomal recessive optic atrophy	DISP0XVX	Supportive	Autosomal recessive	[1]
Optic nerve disorder	DISSOQM8	Limited	Genetic Variation	[3]

14 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 Reticulon-4-interacting protein 1, mitochondrial (RTN4IP1).	[4]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Reticulon-4-interacting protein 1, mitochondrial (RTN4IP1).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Reticulon-4-interacting protein 1, mitochondrial (RTN4IP1).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Reticulon-4-interacting protein 1, mitochondrial (RTN4IP1).	[7]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Reticulon-4-interacting protein 1, mitochondrial (RTN4IP1).	[8]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Reticulon-4-interacting protein 1, mitochondrial (RTN4IP1).	[9]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Reticulon-4-interacting protein 1, mitochondrial (RTN4IP1).	[10]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Reticulon-4-interacting protein 1, mitochondrial (RTN4IP1).	[11]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Reticulon-4-interacting protein 1, mitochondrial (RTN4IP1).	[12]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Reticulon-4-interacting protein 1, mitochondrial (RTN4IP1).	[13]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Reticulon-4-interacting protein 1, mitochondrial (RTN4IP1).	[14]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Reticulon-4-interacting protein 1, mitochondrial (RTN4IP1).	[16]
Deguelin	DMXT7WG	Investigative	Deguelin decreases the expression of Reticulon-4-interacting protein 1, mitochondrial (RTN4IP1).	[17]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate decreases the expression of Reticulon-4-interacting protein 1, mitochondrial (RTN4IP1).	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
DNCB	DMDTVYC	Phase 2	DNCB affects the binding of Reticulon-4-interacting protein 1, mitochondrial (RTN4IP1).	[15]

References

• [1] Recessive Mutations in RTN4IP1 Cause Isolated and Syndromic Optic Neuropathies. Am J Hum Genet. 2015 Nov 5;97(5):754-60. doi: 10.1016/j.ajhg.2015.09.012. Epub 2015 Oct 22.
• [2] RTN4IP1 is down-regulated in thyroid cancer and has tumor-suppressive function.J Clin Endocrinol Metab. 2013 Mar;98(3):E446-54. doi: 10.1210/jc.2012-3180. Epub 2013 Feb 7.
• [3] Siblings with optic neuropathy and RTN4IP1 mutation.J Hum Genet. 2017 Oct;62(10):927-929. doi: 10.1038/jhg.2017.68. Epub 2017 Jun 22.
• [4] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [5] 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.
• [6] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [7] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [8] 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.
• [9] 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.
• [10] 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.
• [11] 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.
• [12] 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.
• [13] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [14] 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.
• [15] Proteomic analysis of the cellular response to a potent sensitiser unveils the dynamics of haptenation in living cells. Toxicology. 2020 Dec 1;445:152603. doi: 10.1016/j.tox.2020.152603. Epub 2020 Sep 28.
• [16] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [17] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.
• [18] Transcriptome dynamics of alternative splicing events revealed early phase of apoptosis induced by methylparaben in H1299 human lung carcinoma cells. Arch Toxicol. 2020 Jan;94(1):127-140. doi: 10.1007/s00204-019-02629-w. Epub 2019 Nov 20.