Details of Drug Off-Target (DOT)

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

• DOT Name: Mitochondrial uncoupling protein 4 (SLC25A27)
• Synonyms: UCP 4; Solute carrier family 25 member 27
• Gene Name: SLC25A27
• UniProt ID: UCP4_HUMAN
• Pfam ID: PF00153
• Sequence:
  MSVPEEEERLLPLTQRWPRASKFLLSGCAATVAELATFPLDLTKTRLQMQGEAALARLGD
  GARESAPYRGMVRTALGIIEEEGFLKLWQGVTPAIYRHVVYSGGRMVTYEHLREVVFGKS
  EDEHYPLWKSVIGGMMAGVIGQFLANPTDLVKVQMQMEGKRKLEGKPLRFRGVHHAFAKI
  LAEGGIRGLWAGWVPNIQRAALVNMGDLTTYDTVKHYLVLNTPLEDNIMTHGLSSLCSGL
  VASILGTPADVIKSRIMNQPRDKQGRGLLYKSSTDCLIQAVQGEGFMSLYKGFLPSWLRM
  TPWSMVFWLTYEKIREMSGVSPF
• Function: Facilitates proton transport across the inner mitochondrial membrane and may dissipate excessive proton gradient associated with oxidative and metabolic stress at neuronal synapses. Regulates glutamate-induced proton conductance in astrocytes, shifting the energy metabolism toward aerobic glycolysis and lactate transfer to neurons for ATP synthesis. Can transport chloride ions with lower efficiency. The transport mechanism remains to be elucidated.
• Tissue Specificity: Found in adult and fetal brain. Present in most of the brain tissues, with low levels in spinal chord, corpus callosum and substantia nigra.
• Reactome Pathway:
  The proton buffering model (R-HSA-167827)
  The fatty acid cycling model (R-HSA-167826)

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Mitochondrial uncoupling protein 4 (SLC25A27).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Mitochondrial uncoupling protein 4 (SLC25A27).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Mitochondrial uncoupling protein 4 (SLC25A27).	[3]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Mitochondrial uncoupling protein 4 (SLC25A27).	[4]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Mitochondrial uncoupling protein 4 (SLC25A27).	[5]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil decreases the expression of Mitochondrial uncoupling protein 4 (SLC25A27).	[6]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Mitochondrial uncoupling protein 4 (SLC25A27).	[7]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Mitochondrial uncoupling protein 4 (SLC25A27).	[8]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Mitochondrial uncoupling protein 4 (SLC25A27).	[9]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Mitochondrial uncoupling protein 4 (SLC25A27).	[10]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Mitochondrial uncoupling protein 4 (SLC25A27).	[11]
4-hydroxy-2-nonenal	DM2LJFZ	Investigative	4-hydroxy-2-nonenal decreases the expression of Mitochondrial uncoupling protein 4 (SLC25A27).	[12]
Cycloheximide	DMGDA3C	Investigative	Cycloheximide increases the expression of Mitochondrial uncoupling protein 4 (SLC25A27).	[12]

References

• [1] 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.
• [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] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [4] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [5] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [6] New insights into the mechanisms underlying 5-fluorouracil-induced intestinal toxicity based on transcriptomic and metabolomic responses in human intestinal organoids. Arch Toxicol. 2021 Aug;95(8):2691-2718. doi: 10.1007/s00204-021-03092-2. Epub 2021 Jun 20.
• [7] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [8] 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.
• [9] Comparison of transcriptome expression alterations by chronic exposure to low-dose bisphenol A in different subtypes of breast cancer cells. Toxicol Appl Pharmacol. 2019 Dec 15;385:114814. doi: 10.1016/j.taap.2019.114814. Epub 2019 Nov 9.
• [10] 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.
• [11] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [12] Transcriptional regulation of UCP4 by NF-kappaB and its role in mediating protection against MPP+ toxicity. Free Radic Biol Med. 2010 Jul 15;49(2):192-204. doi: 10.1016/j.freeradbiomed.2010.04.002. Epub 2010 Apr 9.