Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT6CLFXB)

• DOT Name: Mitochondrial carnitine/acylcarnitine carrier protein (SLC25A20)
• Synonyms: Carnitine/acylcarnitine translocase; CAC; CACT; Solute carrier family 25 member 20
• Gene Name: SLC25A20
• Related Disease: Carnitine-acylcarnitine translocase deficiency
• UniProt ID: MCAT_HUMAN
• Pfam ID: PF00153
• Sequence:
  MADQPKPISPLKNLLAGGFGGVCLVFVGHPLDTVKVRLQTQPPSLPGQPPMYSGTFDCFR
  KTLFREGITGLYRGMAAPIIGVTPMFAVCFFGFGLGKKLQQKHPEDVLSYPQLFAAGMLS
  GVFTTGIMTPGERIKCLLQIQASSGESKYTGTLDCAKKLYQEFGIRGIYKGTVLTLMRDV
  PASGMYFMTYEWLKNIFTPEGKRVSELSAPRILVAGGIAGIFNWAVAIPPDVLKSRFQTA
  PPGKYPNGFRDVLRELIRDEGVTSLYKGFNAVMIRAFPANAACFLGFEVAMKFLNWATPN
  L
• Function: Mediates the electroneutral exchange of acylcarnitines (O-acyl-(R)-carnitine or L-acylcarnitine) of different acyl chain lengths (ranging from O-acetyl-(R)-carnitine to long-chain O-acyl-(R)-carnitines) with free carnitine ((R)-carnitine or L-carnitine) across the mitochondrial inner membrane, via a ping-pong mechanism (Probable). Key player in the mitochondrial oxidation pathway, it translocates the fatty acids in the form of acylcarnitines into the mitochondrial matrix, where the carnitine palmitoyltransferase 2 (CPT-2) activates them to undergo fatty acid beta-oxidation (Probable). Catalyzes the unidirectional transport (uniport) of carnitine at lower rates than the antiport (exchange).
• KEGG Pathway: Thermogenesis (hsa04714)
• Reactome Pathway: Carnitine metabolism (R-HSA-200425)
• BioCyc Pathway: MetaCyc:ENSG00000178537-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Carnitine-acylcarnitine translocase deficiency	DISR2O7P	Definitive	Autosomal recessive	[1]

2 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 carnitine/acylcarnitine carrier protein (SLC25A20).	[2]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Mitochondrial carnitine/acylcarnitine carrier protein (SLC25A20).	[8]

22 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 carnitine/acylcarnitine carrier protein (SLC25A20).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Mitochondrial carnitine/acylcarnitine carrier protein (SLC25A20).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Mitochondrial carnitine/acylcarnitine carrier protein (SLC25A20).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Mitochondrial carnitine/acylcarnitine carrier protein (SLC25A20).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Mitochondrial carnitine/acylcarnitine carrier protein (SLC25A20).	[7]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Mitochondrial carnitine/acylcarnitine carrier protein (SLC25A20).	[3]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Mitochondrial carnitine/acylcarnitine carrier protein (SLC25A20).	[9]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Mitochondrial carnitine/acylcarnitine carrier protein (SLC25A20).	[10]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Mitochondrial carnitine/acylcarnitine carrier protein (SLC25A20).	[10]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone decreases the expression of Mitochondrial carnitine/acylcarnitine carrier protein (SLC25A20).	[7]
Cidofovir	DMA13GD	Approved	Cidofovir increases the expression of Mitochondrial carnitine/acylcarnitine carrier protein (SLC25A20).	[7]
Fenofibrate	DMFKXDY	Approved	Fenofibrate increases the expression of Mitochondrial carnitine/acylcarnitine carrier protein (SLC25A20).	[11]
Zidovudine	DM4KI7O	Approved	Zidovudine increases the expression of Mitochondrial carnitine/acylcarnitine carrier protein (SLC25A20).	[12]
Ifosfamide	DMCT3I8	Approved	Ifosfamide increases the expression of Mitochondrial carnitine/acylcarnitine carrier protein (SLC25A20).	[7]
Clodronate	DM9Y6X7	Approved	Clodronate increases the expression of Mitochondrial carnitine/acylcarnitine carrier protein (SLC25A20).	[7]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Mitochondrial carnitine/acylcarnitine carrier protein (SLC25A20).	[13]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Mitochondrial carnitine/acylcarnitine carrier protein (SLC25A20).	[14]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Mitochondrial carnitine/acylcarnitine carrier protein (SLC25A20).	[15]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Mitochondrial carnitine/acylcarnitine carrier protein (SLC25A20).	[16]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of Mitochondrial carnitine/acylcarnitine carrier protein (SLC25A20).	[17]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Mitochondrial carnitine/acylcarnitine carrier protein (SLC25A20).	[18]
GW7647	DM9RD0C	Investigative	GW7647 increases the expression of Mitochondrial carnitine/acylcarnitine carrier protein (SLC25A20).	[19]

References

• [1] 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.
• [2] Integrated 'omics analysis reveals new drug-induced mitochondrial perturbations in human hepatocytes. Toxicol Lett. 2018 Jun 1;289:1-13.
• [3] 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.
• [4] 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.
• [5] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] Transcriptomics hit the target: monitoring of ligand-activated and stress response pathways for chemical testing. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):7-18.
• [8] 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.
• [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] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [11] Transcriptomic analysis of untreated and drug-treated differentiated HepaRG cells over a 2-week period. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):27-35.
• [12] 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.
• [13] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [14] 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.
• [15] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [16] 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.
• [17] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [18] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
• [19] Farnesol induces fatty acid oxidation and decreases triglyceride accumulation in steatotic HepaRG cells. Toxicol Appl Pharmacol. 2019 Feb 15;365:61-70.