Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTT8647H)

• DOT Name: Mitochondrial dicarboxylate carrier (SLC25A10)
• Synonyms: DIC; Solute carrier family 25 member 10
• Gene Name: SLC25A10
• Related Disease:
  Mitochondrial DNA depletion syndrome 19
  Mitochondrial disease
• UniProt ID: DIC_HUMAN
• Pfam ID: PF00153
• Sequence:
  MAAEARVSRWYFGGLASCGAACCTHPLDLLKVHLQTQQEVKLRMTGMALRVVRTDGILAL
  YSGLSASLCRQMTYSLTRFAIYETVRDRVAKGSQGPLPFHEKVLLGSVSGLAGGFVGTPA
  DLVNVRMQNDVKLPQGQRRNYAHALDGLYRVAREEGLRRLFSGATMASSRGALVTVGQLS
  CYDQAKQLVLSTGYLSDNIFTHFVASFIAGGCATFLCQPLDVLKTRLMNSKGEYQGVFHC
  AVETAKLGPLAFYKGLVPAGIRLIPHTVLTFVFLEQLRKNFGIKVPS
• Function: Catalyzes the electroneutral exchange or flux of physiologically important metabolites such as dicarboxylates (malonate, malate, succinate), inorganic sulfur-containing anions, and phosphate, across mitochondrial inner membrane. Plays an important role in gluconeogenesis, fatty acid metabolism, urea synthesis, and sulfur metabolism, particularly in liver, by supplying the substrates for the different metabolic processes. Regulates fatty acid release from adipocytes, and contributes to systemic insulin sensitivity.
• Tissue Specificity: Present in high amounts in liver and kidney, and at lower levels in all the other tissues analyzed.
• KEGG Pathway: Proximal tubule bicarbo.te reclamation (hsa04964)
• Reactome Pathway:
  Organic anion transporters (R-HSA-428643)
  Gluconeogenesis (R-HSA-70263)
  Sulfide oxidation to sulfate (R-HSA-1614517)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Mitochondrial DNA depletion syndrome 19	DISVP6VZ	Moderate	Autosomal recessive	[1]
Mitochondrial disease	DISKAHA3	Limited	Autosomal recessive	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Mitochondrial dicarboxylate carrier (SLC25A10).	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Mitochondrial dicarboxylate carrier (SLC25A10).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Mitochondrial dicarboxylate carrier (SLC25A10).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen affects the expression of Mitochondrial dicarboxylate carrier (SLC25A10).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Mitochondrial dicarboxylate carrier (SLC25A10).	[7]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Mitochondrial dicarboxylate carrier (SLC25A10).	[8]
Troglitazone	DM3VFPD	Approved	Troglitazone decreases the expression of Mitochondrial dicarboxylate carrier (SLC25A10).	[9]
Obeticholic acid	DM3Q1SM	Approved	Obeticholic acid decreases the expression of Mitochondrial dicarboxylate carrier (SLC25A10).	[10]
Zidovudine	DM4KI7O	Approved	Zidovudine increases the expression of Mitochondrial dicarboxylate carrier (SLC25A10).	[11]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Mitochondrial dicarboxylate carrier (SLC25A10).	[12]
GSK2110183	DMZHB37	Phase 2	GSK2110183 decreases the expression of Mitochondrial dicarboxylate carrier (SLC25A10).	[13]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Mitochondrial dicarboxylate carrier (SLC25A10).	[4]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of Mitochondrial dicarboxylate carrier (SLC25A10).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Mitochondrial dicarboxylate carrier (SLC25A10).	[15]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Mitochondrial dicarboxylate carrier (SLC25A10).	[16]

References

• [1] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [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] 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.
• [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] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [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] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [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] Effects of ciglitazone and troglitazone on the proliferation of human stomach cancer cells. World J Gastroenterol. 2009 Jan 21;15(3):310-20.
• [10] Pharmacotoxicology of clinically-relevant concentrations of obeticholic acid in an organotypic human hepatocyte system. Toxicol In Vitro. 2017 Mar;39:93-103.
• [11] Differential gene expression in human hepatocyte cell lines exposed to the antiretroviral agent zidovudine. Arch Toxicol. 2014 Mar;88(3):609-23. doi: 10.1007/s00204-013-1169-3. Epub 2013 Nov 30.
• [12] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [13] Novel ATP-competitive Akt inhibitor afuresertib suppresses the proliferation of malignant pleural mesothelioma cells. Cancer Med. 2017 Nov;6(11):2646-2659. doi: 10.1002/cam4.1179. Epub 2017 Sep 27.
• [14] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [15] Comprehensive analysis of transcriptomic changes induced by low and high doses of bisphenol A in HepG2 spheroids in vitro and rat liver in vivo. Environ Res. 2019 Jun;173:124-134. doi: 10.1016/j.envres.2019.03.035. Epub 2019 Mar 18.
• [16] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.