Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT1U2GWG)

• DOT Name: N(G),N(G)-dimethylarginine dimethylaminohydrolase 1 (DDAH1)
• Synonyms: DDAH-1; Dimethylarginine dimethylaminohydrolase 1; EC 3.5.3.18; DDAHI; Dimethylargininase-1
• Gene Name: DDAH1
• UniProt ID: DDAH1_HUMAN
• PDB ID: 2JAI; 2JAJ; 3I2E; 3I4A; 3P8E; 3P8P; 6DGE; 6SZP; 6SZQ; 7ULU; 7ULV; 7ULX; 7USZ; 7UT0
• EC Number: 3.5.3.18
• Pfam ID: PF19420
• Sequence:
  MAGLGHPAAFGRATHAVVRALPESLGQHALRSAKGEEVDVARAERQHQLYVGVLGSKLGL
  QVVELPADESLPDCVFVEDVAVVCEETALITRPGAPSRRKEVDMMKEALEKLQLNIVEMK
  DENATLDGGDVLFTGREFFVGLSKRTNQRGAEILADTFKDYAVSTVPVADGLHLKSFCSM
  AGPNLIAIGSSESAQKALKIMQQMSDHRYDKLTVPDDIAANCIYLNIPNKGHVLLHRTPE
  EYPESAKVYEKLKDHMLIPVSMSELEKVDGLLTCCSVLINKKVDS
• Function: Hydrolyzes N(G),N(G)-dimethyl-L-arginine (ADMA) and N(G)-monomethyl-L-arginine (MMA) which act as inhibitors of NOS. Has therefore a role in the regulation of nitric oxide generation.
• Tissue Specificity: Detected in brain, liver, kidney and pancreas, and at low levels in skeletal muscle.
• Reactome Pathway: eNOS activation (R-HSA-203615)
• BioCyc Pathway: MetaCyc:HS00016-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

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 N(G),N(G)-dimethylarginine dimethylaminohydrolase 1 (DDAH1).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of N(G),N(G)-dimethylarginine dimethylaminohydrolase 1 (DDAH1).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of N(G),N(G)-dimethylarginine dimethylaminohydrolase 1 (DDAH1).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of N(G),N(G)-dimethylarginine dimethylaminohydrolase 1 (DDAH1).	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of N(G),N(G)-dimethylarginine dimethylaminohydrolase 1 (DDAH1).	[5]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of N(G),N(G)-dimethylarginine dimethylaminohydrolase 1 (DDAH1).	[6]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of N(G),N(G)-dimethylarginine dimethylaminohydrolase 1 (DDAH1).	[7]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of N(G),N(G)-dimethylarginine dimethylaminohydrolase 1 (DDAH1).	[8]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of N(G),N(G)-dimethylarginine dimethylaminohydrolase 1 (DDAH1).	[9]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of N(G),N(G)-dimethylarginine dimethylaminohydrolase 1 (DDAH1).	[10]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of N(G),N(G)-dimethylarginine dimethylaminohydrolase 1 (DDAH1).	[11]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of N(G),N(G)-dimethylarginine dimethylaminohydrolase 1 (DDAH1).	[12]
Hydroquinone	DM6AVR4	Approved	Hydroquinone decreases the expression of N(G),N(G)-dimethylarginine dimethylaminohydrolase 1 (DDAH1).	[13]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of N(G),N(G)-dimethylarginine dimethylaminohydrolase 1 (DDAH1).	[15]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of N(G),N(G)-dimethylarginine dimethylaminohydrolase 1 (DDAH1).	[17]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of N(G),N(G)-dimethylarginine dimethylaminohydrolase 1 (DDAH1).	[18]
Taurine	DMVW7N3	Investigative	Taurine decreases the expression of N(G),N(G)-dimethylarginine dimethylaminohydrolase 1 (DDAH1).	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of N(G),N(G)-dimethylarginine dimethylaminohydrolase 1 (DDAH1).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of N(G),N(G)-dimethylarginine dimethylaminohydrolase 1 (DDAH1).	[16]

References

• [1] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [2] 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.
• [3] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [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] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [6] Identification of novel low-dose bisphenol a targets in human foreskin fibroblast cells derived from hypospadias patients. PLoS One. 2012;7(5):e36711. doi: 10.1371/journal.pone.0036711. Epub 2012 May 4.
• [7] 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.
• [8] 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.
• [9] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [10] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [11] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [12] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [13] Keratinocyte-derived IL-36gama plays a role in hydroquinone-induced chemical leukoderma through inhibition of melanogenesis in human epidermal melanocytes. Arch Toxicol. 2019 Aug;93(8):2307-2320.
• [14] 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.
• [15] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [16] 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.
• [17] 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.
• [18] Identification of gene markers for formaldehyde exposure in humans. Environ Health Perspect. 2007 Oct;115(10):1460-6. doi: 10.1289/ehp.10180.
• [19] Taurine-responsive genes related to signal transduction as identified by cDNA microarray analyses of HepG2 cells. J Med Food. 2006 Spring;9(1):33-41. doi: 10.1089/jmf.2006.9.33.