Details of Drug Off-Target (DOT)

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

• DOT Name: Microsomal triglyceride transfer protein large subunit (MTTP)
• Gene Name: MTTP
• Related Disease: Abetalipoproteinemia
• UniProt ID: MTP_HUMAN
• PDB ID: 8EOJ
• Pfam ID: PF19444 ; PF01347
• Sequence:
  MILLAVLFLCFISSYSASVKGHTTGLSLNNDRLYKLTYSTEVLLDRGKGKLQDSVGYRIS
  SNVDVALLWRNPDGDDDQLIQITMKDVNVENVNQQRGEKSIFKGKSPSKIMGKENLEALQ
  RPTLLHLIHGKVKEFYSYQNEAVAIENIKRGLASLFQTQLSSGTTNEVDISGNCKVTYQA
  HQDKVIKIKALDSCKIARSGFTTPNQVLGVSSKATSVTTYKIEDSFVIAVLAEETHNFGL
  NFLQTIKGKIVSKQKLELKTTEAGPRLMSGKQAAAIIKAVDSKYTAIPIVGQVFQSHCKG
  CPSLSELWRSTRKYLQPDNLSKAEAVRNFLAFIQHLRTAKKEEILQILKMENKEVLPQLV
  DAVTSAQTSDSLEAILDFLDFKSDSSIILQERFLYACGFASHPNEELLRALISKFKGSIG
  SSDIRETVMIITGTLVRKLCQNEGCKLKAVVEAKKLILGGLEKAEKKEDTRMYLLALKNA
  LLPEGIPSLLKYAEAGEGPISHLATTALQRYDLPFITDEVKKTLNRIYHQNRKVHEKTVR
  TAAAAIILNNNPSYMDVKNILLSIGELPQEMNKYMLAIVQDILRFEMPASKIVRRVLKEM
  VAHNYDRFSRSGSSSAYTGYIERSPRSASTYSLDILYSGSGILRRSNLNIFQYIGKAGLH
  GSQVVIEAQGLEALIAATPDEGEENLDSYAGMSAILFDVQLRPVTFFNGYSDLMSKMLSA
  SGDPISVVKGLILLIDHSQELQLQSGLKANIEVQGGLAIDISGAMEFSLWYRESKTRVKN
  RVTVVITTDITVDSSFVKAGLETSTETEAGLEFISTVQFSQYPFLVCMQMDKDEAPFRQF
  EKKYERLSTGRGYVSQKRKESVLAGCEFPLHQENSEMCKVVFAPQPDSTSSGWF
• Function: Catalyzes the transport of triglyceride, cholesteryl ester, and phospholipid between phospholipid surfaces. Required for the assembly and secretion of plasma lipoproteins that contain apolipoprotein B. May be involved in regulating cholesteryl ester biosynthesis in cells that produce lipoproteins.
• Tissue Specificity: Liver and small intestine. Also found in ovary, testis and kidney.
• KEGG Pathway: Fat digestion and absorption (hsa04975)
• Reactome Pathway:
  Chylomicron assembly (R-HSA-8963888)
  LDL remodeling (R-HSA-8964041)
  VLDL assembly (R-HSA-8866423)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Abetalipoproteinemia	DISMSS7T	Definitive	Autosomal recessive	[1]

31 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 Microsomal triglyceride transfer protein large subunit (MTTP).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Microsomal triglyceride transfer protein large subunit (MTTP).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Microsomal triglyceride transfer protein large subunit (MTTP).	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Microsomal triglyceride transfer protein large subunit (MTTP).	[5]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Microsomal triglyceride transfer protein large subunit (MTTP).	[3]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Microsomal triglyceride transfer protein large subunit (MTTP).	[6]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil decreases the expression of Microsomal triglyceride transfer protein large subunit (MTTP).	[7]
Troglitazone	DM3VFPD	Approved	Troglitazone decreases the expression of Microsomal triglyceride transfer protein large subunit (MTTP).	[7]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone increases the expression of Microsomal triglyceride transfer protein large subunit (MTTP).	[8]
Aspirin	DM672AH	Approved	Aspirin decreases the expression of Microsomal triglyceride transfer protein large subunit (MTTP).	[9]
Indomethacin	DMSC4A7	Approved	Indomethacin decreases the expression of Microsomal triglyceride transfer protein large subunit (MTTP).	[7]
Rifampicin	DM5DSFZ	Approved	Rifampicin decreases the expression of Microsomal triglyceride transfer protein large subunit (MTTP).	[7]
Sulindac	DM2QHZU	Approved	Sulindac increases the expression of Microsomal triglyceride transfer protein large subunit (MTTP).	[7]
Bosentan	DMIOGBU	Approved	Bosentan decreases the expression of Microsomal triglyceride transfer protein large subunit (MTTP).	[10]
Deoxycholic acid	DM3GYAL	Approved	Deoxycholic acid decreases the expression of Microsomal triglyceride transfer protein large subunit (MTTP).	[9]
Tetracycline	DMZA017	Approved	Tetracycline decreases the expression of Microsomal triglyceride transfer protein large subunit (MTTP).	[9]
Clofibrate	DMPC1J7	Approved	Clofibrate decreases the expression of Microsomal triglyceride transfer protein large subunit (MTTP).	[9]
Allopurinol	DMLPAOB	Approved	Allopurinol decreases the expression of Microsomal triglyceride transfer protein large subunit (MTTP).	[7]
Tolcapone	DM8MNVO	Approved	Tolcapone increases the expression of Microsomal triglyceride transfer protein large subunit (MTTP).	[11]
Indinavir	DM0T3YH	Approved	Indinavir decreases the expression of Microsomal triglyceride transfer protein large subunit (MTTP).	[7]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Microsomal triglyceride transfer protein large subunit (MTTP).	[12]
Atorvastatin	DMF28YC	Phase 3 Trial	Atorvastatin decreases the expression of Microsomal triglyceride transfer protein large subunit (MTTP).	[13]
Chloroquine	DMSI5CB	Phase 3 Trial	Chloroquine increases the expression of Microsomal triglyceride transfer protein large subunit (MTTP).	[14]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone decreases the expression of Microsomal triglyceride transfer protein large subunit (MTTP).	[9]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of Microsomal triglyceride transfer protein large subunit (MTTP).	[7]
MG-132	DMKA2YS	Preclinical	MG-132 increases the expression of Microsomal triglyceride transfer protein large subunit (MTTP).	[14]
Taxifolin	DMQJSF9	Preclinical	Taxifolin decreases the activity of Microsomal triglyceride transfer protein large subunit (MTTP).	[16]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Microsomal triglyceride transfer protein large subunit (MTTP).	[17]
Oleic acid	DM54O1Z	Investigative	Oleic acid decreases the expression of Microsomal triglyceride transfer protein large subunit (MTTP).	[18]
T0901317	DMZQVDI	Investigative	T0901317 decreases the expression of Microsomal triglyceride transfer protein large subunit (MTTP).	[19]
Bafilomycin A1	DMUNK59	Investigative	Bafilomycin A1 increases the expression of Microsomal triglyceride transfer protein large subunit (MTTP).	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Microsomal triglyceride transfer protein large subunit (MTTP).	[15]

References

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• [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.
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• [7] Drug-induced hepatic steatosis in absence of severe mitochondrial dysfunction in HepaRG cells: proof of multiple mechanism-based toxicity. Cell Biol Toxicol. 2021 Apr;37(2):151-175. doi: 10.1007/s10565-020-09537-1. Epub 2020 Jun 14.
• [8] Replacement per- and polyfluoroalkyl substances (PFAS) are potent modulators of lipogenic and drug metabolizing gene expression signatures in primary human hepatocytes. Toxicol Appl Pharmacol. 2022 May 1;442:115991. doi: 10.1016/j.taap.2022.115991. Epub 2022 Mar 23.
• [9] Advantageous use of HepaRG cells for the screening and mechanistic study of drug-induced steatosis. Toxicol Appl Pharmacol. 2016 Jul 1;302:1-9. doi: 10.1016/j.taap.2016.04.007. Epub 2016 Apr 16.
• [10] Omics-based responses induced by bosentan in human hepatoma HepaRG cell cultures. Arch Toxicol. 2018 Jun;92(6):1939-1952.
• [11] Effect of the Catechol-O-Methyltransferase Inhibitors Tolcapone and Entacapone on Fatty Acid Metabolism in HepaRG Cells. Toxicol Sci. 2018 Aug 1;164(2):477-488.
• [12] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [13] Differential regulation of apolipoprotein B secretion from HepG2 cells by two HMG-CoA reductase inhibitors, atorvastatin and simvastatin. J Lipid Res. 1999 Jun;40(6):1078-89.
• [14] Cadmium induces triglyceride levels via microsomal triglyceride transfer protein (MTTP) accumulation caused by lysosomal deacidification regulated by endoplasmic reticulum (ER) Ca(2+) homeostasis. Chem Biol Interact. 2021 Oct 1;348:109649. doi: 10.1016/j.cbi.2021.109649. Epub 2021 Sep 10.
• [15] 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.
• [16] Inhibitory activity of diacylglycerol acyltransferase (DGAT) and microsomal triglyceride transfer protein (MTP) by the flavonoid, taxifolin, in HepG2 cells: potential role in the regulation of apolipoprotein B secretion. Atherosclerosis. 2004 Oct;176(2):247-53. doi: 10.1016/j.atherosclerosis.2004.05.020.
• [17] Downregulation of miR-192 causes hepatic steatosis and lipid accumulation by inducing SREBF1: Novel mechanism for bisphenol A-triggered non-alcoholic fatty liver disease. Biochim Biophys Acta Mol Cell Biol Lipids. 2017 Sep;1862(9):869-882. doi: 10.1016/j.bbalip.2017.05.001. Epub 2017 May 5.
• [18] Farnesol induces fatty acid oxidation and decreases triglyceride accumulation in steatotic HepaRG cells. Toxicol Appl Pharmacol. 2019 Feb 15;365:61-70.
• [19] Isosilybin regulates lipogenesis and fatty acid oxidation via the AMPK/SREBP-1c/PPAR pathway. Chem Biol Interact. 2022 Dec 1;368:110250. doi: 10.1016/j.cbi.2022.110250. Epub 2022 Nov 5.