Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT7P1WMM)

• DOT Name: Solute carrier family 25 member 33 (SLC25A33)
• Synonyms: Bone marrow stromal cell mitochondrial carrier protein; BMSC-MCP; HuBMSC-MCP; Protein PNC1
• Gene Name: SLC25A33
• UniProt ID: S2533_HUMAN
• Pfam ID: PF00153
• Sequence:
  MATGGQQKENTLLHLFAGGCGGTVGAIFTCPLEVIKTRLQSSRLALRTVYYPQVHLGTIS
  GAGMVRPTSVTPGLFQVLKSILEKEGPKSLFRGLGPNLVGVAPSRAVYFACYSKAKEQFN
  GIFVPNSNIVHIFSAGSAAFITNSLMNPIWMVKTRMQLEQKVRGSKQMNTLQCARYVYQT
  EGIRGFYRGLTASYAGISETIICFAIYESLKKYLKEAPLASSANGTEKNSTSFFGLMAAA
  ALSKGCASCIAYPHEVIRTRLREEGTKYKSFVQTARLVFREEGYLAFYRGLFAQLIRQIP
  NTAIVLSTYELIVYLLEDRTQ
• Function: Mitochondrial transporter that imports/exports pyrimidine nucleotides into and from mitochondria. Selectively transports uridine, thymidine, guanosine, cytosine and inosine (deoxy)nucleoside di- and triphosphates by an antiport mechanism. May import (deoxy)nucleoside triphosphates in exchange for intramitochondrial (deoxy)nucleoside diphosphates, thus providing precursors necessary for de novo synthesis of mitochondrial DNA and RNA while exporting products of their catabolism. Participates in mitochondrial genome maintenance, regulation of mitochondrial membrane potential and mitochondrial respiration. Upon INS or IGF1 stimulation regulates cell growth and proliferation by controlling mitochondrial DNA replication and transcription, the ratio of mitochondria-to nuclear-encoded components of the electron transport chain resulting in control of mitochondrial ROS production. Participates in dendritic cell endocytosis and may associate with mitochondrial oxidative phosphorylation.
• Tissue Specificity: Expressed in the central nervous system. Also expressed in testis and skeletal muscle. Weakly expressed in heart, liver, kidney, prostate, colon and peripheral blood leukocytes.

Molecular Interaction Atlas (MIA) of This DOT

10 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 Solute carrier family 25 member 33 (SLC25A33).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Solute carrier family 25 member 33 (SLC25A33).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Solute carrier family 25 member 33 (SLC25A33).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Solute carrier family 25 member 33 (SLC25A33).	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Solute carrier family 25 member 33 (SLC25A33).	[5]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Solute carrier family 25 member 33 (SLC25A33).	[6]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Solute carrier family 25 member 33 (SLC25A33).	[8]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Solute carrier family 25 member 33 (SLC25A33).	[9]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Solute carrier family 25 member 33 (SLC25A33).	[10]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Solute carrier family 25 member 33 (SLC25A33).	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Solute carrier family 25 member 33 (SLC25A33).	[7]

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] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [5] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [6] 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.
• [7] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [8] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [9] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [10] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [11] 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.