Details of Drug Off-Target (DOT)

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

• DOT Name: 3-hydroxyisobutyrate dehydrogenase, mitochondrial (HIBADH)
• Synonyms: HIBADH; EC 1.1.1.31
• Gene Name: HIBADH
• Related Disease:
  Cardiovascular disease
  3-hydroxyisobutyric aciduria
• UniProt ID: 3HIDH_HUMAN
• PDB ID: 2GF2; 2I9P
• EC Number: 1.1.1.31
• Pfam ID: PF14833 ; PF03446
• Sequence:
  MAASLRLLGAASGLRYWSRRLRPAAGSFAAVCSRSVASKTPVGFIGLGNMGNPMAKNLMK
  HGYPLIIYDVFPDACKEFQDAGEQVVSSPADVAEKADRIITMLPTSINAIEAYSGANGIL
  KKVKKGSLLIDSSTIDPAVSKELAKEVEKMGAVFMDAPVSGGVGAARSGNLTFMVGGVED
  EFAAAQELLGCMGSNVVYCGAVGTGQAAKICNNMLLAISMIGTAEAMNLGIRLGLDPKLL
  AKILNMSSGRCWSSDTYNPVPGVMDGVPSANNYQGGFGTTLMAKDLGLAQDSATSTKSPI
  LLGSLAHQIYRMMCAKGYSKKDFSSVFQFLREEETF
• Tissue Specificity: Detected in skin fibroblasts.
• KEGG Pathway:
  Valine, leucine and isoleucine degradation (hsa00280)
  Metabolic pathways (hsa01100)
• Reactome Pathway: Branched-chain amino acid catabolism (R-HSA-70895)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cardiovascular disease	DIS2IQDX	Strong	Genetic Variation	[1]
3-hydroxyisobutyric aciduria	DISXIPQ9	Limited	Autosomal recessive	[2]

17 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 3-hydroxyisobutyrate dehydrogenase, mitochondrial (HIBADH).	[3]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of 3-hydroxyisobutyrate dehydrogenase, mitochondrial (HIBADH).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of 3-hydroxyisobutyrate dehydrogenase, mitochondrial (HIBADH).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of 3-hydroxyisobutyrate dehydrogenase, mitochondrial (HIBADH).	[6]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of 3-hydroxyisobutyrate dehydrogenase, mitochondrial (HIBADH).	[7]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of 3-hydroxyisobutyrate dehydrogenase, mitochondrial (HIBADH).	[8]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of 3-hydroxyisobutyrate dehydrogenase, mitochondrial (HIBADH).	[9]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of 3-hydroxyisobutyrate dehydrogenase, mitochondrial (HIBADH).	[10]
Menadione	DMSJDTY	Approved	Menadione affects the expression of 3-hydroxyisobutyrate dehydrogenase, mitochondrial (HIBADH).	[11]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol increases the expression of 3-hydroxyisobutyrate dehydrogenase, mitochondrial (HIBADH).	[13]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of 3-hydroxyisobutyrate dehydrogenase, mitochondrial (HIBADH).	[14]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of 3-hydroxyisobutyrate dehydrogenase, mitochondrial (HIBADH).	[15]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of 3-hydroxyisobutyrate dehydrogenase, mitochondrial (HIBADH).	[4]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of 3-hydroxyisobutyrate dehydrogenase, mitochondrial (HIBADH).	[16]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of 3-hydroxyisobutyrate dehydrogenase, mitochondrial (HIBADH).	[17]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of 3-hydroxyisobutyrate dehydrogenase, mitochondrial (HIBADH).	[18]
[3H]methyltrienolone	DMTSGOW	Investigative	[3H]methyltrienolone decreases the expression of 3-hydroxyisobutyrate dehydrogenase, mitochondrial (HIBADH).	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of 3-hydroxyisobutyrate dehydrogenase, mitochondrial (HIBADH).	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of 3-hydroxyisobutyrate dehydrogenase, mitochondrial (HIBADH).	[12]

References

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• [2] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [3] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [4] 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.
• [5] 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.
• [6] Increased mitochondrial ROS formation by acetaminophen in human hepatic cells is associated with gene expression changes suggesting disruption of the mitochondrial electron transport chain. Toxicol Lett. 2015 Apr 16;234(2):139-50.
• [7] 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.
• [8] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [9] 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.
• [10] Chronic occupational exposure to arsenic induces carcinogenic gene signaling networks and neoplastic transformation in human lung epithelial cells. Toxicol Appl Pharmacol. 2012 Jun 1;261(2):204-16.
• [11] 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.
• [12] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [13] Identification of biomarkers and outcomes of endocrine disruption in human ovarian cortex using In Vitro Models. Toxicology. 2023 Feb;485:153425. doi: 10.1016/j.tox.2023.153425. Epub 2023 Jan 5.
• [14] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [15] 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.
• [16] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [17] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [18] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [19] Evaluation of an in vitro model of androgen ablation and identification of the androgen responsive proteome in LNCaP cells. Proteomics. 2007 Jan;7(1):47-63.