Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTYMJ69D)

• DOT Name: Probable mitochondrial glutathione transporter SLC25A40 (SLC25A40)
• Synonyms: Mitochondrial carrier family protein; Solute carrier family 25 member 40
• Gene Name: SLC25A40
• Related Disease: Squamous cell carcinoma
• UniProt ID: S2540_HUMAN
• Pfam ID: PF00153
• Sequence:
  MDPETRGQEIIKVTPLQQMLASCTGAILTSVIVTPLDVVKIRLQAQNNPLPKGKCFVYSN
  GLMDHLCVCEEGGNKLWYKKPGNFQGTLDAFFKIIRNEGIKSLWSGLPPTLVMAVPATVI
  YFTCYDQLSALLRSKLGENETCIPIVAGIVARFGAVTVISPLELIRTKMQSKKFSYVELH
  RFVSKKVSEDGWISLWRGWAPTVLRDVPFSAMYWYNYEILKKWLCEKSGLYEPTFMINFT
  SGALSGSFAAVATLPFDVVKTQKQTQLWTYESHKISMPLHMSTWIIMKNIVAKNGFSGLF
  SGLIPRLIKIAPACAIMISTYEFGKAFFQKQNVRRQQY
• Function: Probable mitochondrial transporter required for glutathione import into mitochondria. Glutathione, which plays key roles in oxidative metabolism, is produced exclusively in the cytosol and is imported in many organelles. Mitochondrial glutathione is required for the activity and stability of proteins containing iron-sulfur clusters, as well as erythropoiesis.

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Squamous cell carcinoma	DISQVIFL	moderate	Biomarker	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Probable mitochondrial glutathione transporter SLC25A40 (SLC25A40).	[2]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Probable mitochondrial glutathione transporter SLC25A40 (SLC25A40).	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Probable mitochondrial glutathione transporter SLC25A40 (SLC25A40).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Probable mitochondrial glutathione transporter SLC25A40 (SLC25A40).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Probable mitochondrial glutathione transporter SLC25A40 (SLC25A40).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Probable mitochondrial glutathione transporter SLC25A40 (SLC25A40).	[6]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Probable mitochondrial glutathione transporter SLC25A40 (SLC25A40).	[7]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Probable mitochondrial glutathione transporter SLC25A40 (SLC25A40).	[8]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Probable mitochondrial glutathione transporter SLC25A40 (SLC25A40).	[9]
Rifampicin	DM5DSFZ	Approved	Rifampicin decreases the expression of Probable mitochondrial glutathione transporter SLC25A40 (SLC25A40).	[10]
QUERCITRIN	DM1DH96	Investigative	QUERCITRIN decreases the expression of Probable mitochondrial glutathione transporter SLC25A40 (SLC25A40).	[12]

References

• [1] Smooth muscle actin-expressing stromal fibroblasts in head and neck squamous cell carcinoma: increased expression of galectin-1 and induction of poor prognosis factors.Int J Cancer. 2012 Dec 1;131(11):2499-508. doi: 10.1002/ijc.27550. Epub 2012 Apr 9.
• [2] 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.
• [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] 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.
• [5] 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.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [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] 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.
• [9] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [10] Integrated analysis of rifampicin-induced microRNA and gene expression changes in human hepatocytes. Drug Metab Pharmacokinet. 2014;29(4):333-40.
• [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] Molecular mechanisms of quercitrin-induced apoptosis in non-small cell lung cancer. Arch Med Res. 2014 Aug;45(6):445-54.