Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT19H5Q9)

• DOT Name: Rho GTPase-activating protein 8 (ARHGAP8)
• Synonyms: Rho-type GTPase-activating protein 8
• Gene Name: ARHGAP8
• Related Disease:
  Major depressive disorder
  Bipolar disorder
  Breast cancer
  Colorectal carcinoma
  Colorectal neoplasm
• UniProt ID: RHG08_HUMAN
• Pfam ID: PF13716 ; PF00620
• Sequence:
  MAGQDPALSTSHPFYDVARHGILQVAGDDRFGRRVVTFSCCRMPPSHELDHQRLLEYLKY
  TLDQYVENDYTIVYFHYGLNSRNKPSLGWLQSAYKEFDRKDGDLTMWPRLVSNSKLKRSS
  HLSLPKYWDYRYKKNLKALYVVHPTSFIKVLWNILKPLISHKFGKKVIYFNYLSELHEHL
  KYDQLVIPPEVLRYDEKLQSLHEGRTPPPTKTPPPRPPLPTQQFGVSLQYLKDKNQGELI
  PPVLRFTVTYLREKGLRTEGLFRRSASVQTVREIQRLYNQGKPVNFDDYGDIHIPAVILK
  TFLRELPQPLLTFQAYEQILGITCVESSLRVTGCRQILRSLPEHNYVVLRYLMGFLHAVS
  RESIFNKMNSSNLACVFGLNLIWPSQGVSSLSALVPLNMFTELLIEYYEKIFSTPEAPGE
  HGLAPWEQGSRAAPLQEAVPRTQATGLTKPTLPPSPLMAARRRL
• Function: GTPase activator for the Rho-type GTPases by converting them to an inactive GDP-bound state.
• Tissue Specificity: Highly expressed in kidney and placenta. Also expressed in colon, skeletal muscle, small intestine, stomach, and testis. Not detected in brain, liver or spleen. Overexpressed in the majority of colorectal tumors examined.
• Reactome Pathway: RHOA GTPase cycle (R-HSA-8980692)

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Major depressive disorder	DIS4CL3X	Strong	Genetic Variation	[1]
Bipolar disorder	DISAM7J2	moderate	Genetic Variation	[2]
Breast cancer	DIS7DPX1	Limited	Altered Expression	[3]
Colorectal carcinoma	DIS5PYL0	Limited	Genetic Variation	[3]
Colorectal neoplasm	DISR1UCN	Limited	Altered Expression	[3]

10 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 Rho GTPase-activating protein 8 (ARHGAP8).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Rho GTPase-activating protein 8 (ARHGAP8).	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Rho GTPase-activating protein 8 (ARHGAP8).	[6]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Rho GTPase-activating protein 8 (ARHGAP8).	[8]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene increases the expression of Rho GTPase-activating protein 8 (ARHGAP8).	[9]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Rho GTPase-activating protein 8 (ARHGAP8).	[10]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Rho GTPase-activating protein 8 (ARHGAP8).	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Rho GTPase-activating protein 8 (ARHGAP8).	[13]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Rho GTPase-activating protein 8 (ARHGAP8).	[14]
Deguelin	DMXT7WG	Investigative	Deguelin increases the expression of Rho GTPase-activating protein 8 (ARHGAP8).	[15]

2 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 Rho GTPase-activating protein 8 (ARHGAP8).	[7]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Rho GTPase-activating protein 8 (ARHGAP8).	[11]

References

• [1] The PHF21B gene is associated with major depression and modulates the stress response.Mol Psychiatry. 2017 Jul;22(7):1015-1025. doi: 10.1038/mp.2016.174. Epub 2016 Oct 25.
• [2] Bipolar disorder with binge eating behavior: a genome-wide association study implicates PRR5-ARHGAP8.Transl Psychiatry. 2018 Feb 2;8(1):40. doi: 10.1038/s41398-017-0085-3.
• [3] ARHGAP8 is a novel member of the RHOGAP family related to ARHGAP1/CDC42GAP/p50RHOGAP: mutation and expression analyses in colorectal and breast cancers.Gene. 2004 Jul 7;336(1):59-71. doi: 10.1016/j.gene.2004.01.025.
• [4] Stem cell transcriptome responses and corresponding biomarkers that indicate the transition from adaptive responses to cytotoxicity. Chem Res Toxicol. 2017 Apr 17;30(4):905-922.
• [5] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [6] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [7] 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.
• [8] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [9] Induction of class II major histocompatibility complex expression in human multiple myeloma cells by retinoid. Haematologica. 2007 Jan;92(1):115-20.
• [10] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [11] 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.
• [12] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [13] Characterization of the Molecular Alterations Induced by the Prolonged Exposure of Normal Colon Mucosa and Colon Cancer Cells to Low-Dose Bisphenol A. Int J Mol Sci. 2022 Oct 1;23(19):11620. doi: 10.3390/ijms231911620.
• [14] 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.
• [15] 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.