Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTVJJO5Z)

• DOT Name: Phospholipid transfer protein (PLTP)
• Synonyms: Lipid transfer protein II
• Gene Name: PLTP
• UniProt ID: PLTP_HUMAN
• Pfam ID: PF01273 ; PF02886
• Sequence:
  MALFGALFLALLAGAHAEFPGCKIRVTSKALELVKQEGLRFLEQELETITIPDLRGKEGH
  FYYNISEVKVTELQLTSSELDFQPQQELMLQITNASLGLRFRRQLLYWFFYDGGYINASA
  EGVSIRTGLELSRDPAGRMKVSNVSCQASVSRMHAAFGGTFKKVYDFLSTFITSGMRFLL
  NQQICPVLYHAGTVLLNSLLDTVPVRSSVDELVGIDYSLMKDPVASTSNLDMDFRGAFFP
  LTERNWSLPNRAVEPQLQEEERMVYVAFSEFFFDSAMESYFRAGALQLLLVGDKVPHDLD
  MLLRATYFGSIVLLSPAVIDSPLKLELRVLAPPRCTIKPSGTTISVTASVTIALVPPDQP
  EVQLSSMTMDARLSAKMALRGKALRTQLDLRRFRIYSNHSALESLALIPLQAPLKTMLQI
  GVMPMLNERTWRGVQIPLPEGINFVHEVVTNHAGFLTIGADLHFAKGLREVIEKNRPADV
  RASTAPTPSTAAV
• Function: Mediates the transfer of phospholipids and free cholesterol from triglyceride-rich lipoproteins (low density lipoproteins or LDL and very low density lipoproteins or VLDL) into high-density lipoproteins (HDL) as well as the exchange of phospholipids between triglyceride-rich lipoproteins themselves. Facilitates the transfer of a spectrum of different lipid molecules, including diacylglycerol, phosphatidic acid, sphingomyelin, phosphatidylcholine, phosphatidylinositol, phosphatidylglycerol, cerebroside and phosphatidyl ethanolamine. Plays an important role in HDL remodeling which involves modulating the size and composition of HDL. Also plays a key role in the uptake of cholesterol from peripheral cells and tissues that is subsequently transported to the liver for degradation and excretion. Two distinct forms of PLTP exist in plasma: an active form that can transfer phosphatidylcholine from phospholipid vesicles to HDL, and an inactive form that lacks this capability.
• Tissue Specificity: Widely expressed. Highest level of expression in the ovary, thymus and placenta, with moderate levels found in the pancreas, small intestine, testis, lung and prostrate. Low level expression in the kidney, liver and spleen, with very low levels found in the heart, colon, skeletal muscle, leukocytes and brain. Expressed in the cortical neurons.
• KEGG Pathway:
  PPAR sig.ling pathway (hsa03320)
  Cholesterol metabolism (hsa04979)
• Reactome Pathway:
  NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux (R-HSA-9029569)
  HDL remodeling (R-HSA-8964058)

Molecular Interaction Atlas (MIA) of This DOT

19 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 Phospholipid transfer protein (PLTP).	[1]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Phospholipid transfer protein (PLTP).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Phospholipid transfer protein (PLTP).	[3]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Phospholipid transfer protein (PLTP).	[4]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Phospholipid transfer protein (PLTP).	[6]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Phospholipid transfer protein (PLTP).	[7]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Phospholipid transfer protein (PLTP).	[8]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Phospholipid transfer protein (PLTP).	[9]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Phospholipid transfer protein (PLTP).	[10]
Isotretinoin	DM4QTBN	Approved	Isotretinoin increases the expression of Phospholipid transfer protein (PLTP).	[11]
Cytarabine	DMZD5QR	Approved	Cytarabine decreases the expression of Phospholipid transfer protein (PLTP).	[12]
Obeticholic acid	DM3Q1SM	Approved	Obeticholic acid decreases the expression of Phospholipid transfer protein (PLTP).	[13]
Bezafibrate	DMZDCS0	Approved	Bezafibrate decreases the activity of Phospholipid transfer protein (PLTP).	[14]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Phospholipid transfer protein (PLTP).	[15]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Phospholipid transfer protein (PLTP).	[17]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Phospholipid transfer protein (PLTP).	[18]
chloropicrin	DMSGBQA	Investigative	chloropicrin increases the expression of Phospholipid transfer protein (PLTP).	[19]
GW-3965	DMG60ET	Investigative	GW-3965 increases the expression of Phospholipid transfer protein (PLTP).	[20]
T0901317	DMZQVDI	Investigative	T0901317 increases the expression of Phospholipid transfer protein (PLTP).	[20]

2 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 Phospholipid transfer protein (PLTP).	[5]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Phospholipid transfer protein (PLTP).	[16]

References

• [1] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [2] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [3] 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.
• [4] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [5] 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.
• [6] 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.
• [7] 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.
• [8] Global effects of inorganic arsenic on gene expression profile in human macrophages. Mol Immunol. 2009 Feb;46(4):649-56.
• [9] Identification of vitamin D3 target genes in human breast cancer tissue. J Steroid Biochem Mol Biol. 2016 Nov;164:90-97.
• [10] Gene expression profiling of rheumatoid arthritis synovial cells treated with antirheumatic drugs. J Biomol Screen. 2007 Apr;12(3):328-40. doi: 10.1177/1087057107299261. Epub 2007 Mar 22.
• [11] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [12] Cytosine arabinoside induces ectoderm and inhibits mesoderm expression in human embryonic stem cells during multilineage differentiation. Br J Pharmacol. 2011 Apr;162(8):1743-56.
• [13] Pharmacotoxicology of clinically-relevant concentrations of obeticholic acid in an organotypic human hepatocyte system. Toxicol In Vitro. 2017 Mar;39:93-103.
• [14] Decreased PLTP mass but elevated PLTP activity linked to insulin resistance in HTG: effects of bezafibrate therapy. J Lipid Res. 2003 Aug;44(8):1462-9. doi: 10.1194/jlr.M300008-JLR200. Epub 2003 May 16.
• [15] 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.
• [16] 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.
• [17] 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.
• [18] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [19] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.
• [20] Inhibition of progesterone production in human luteinized granulosa cells treated with LXR agonists. Mol Hum Reprod. 2007 Jun;13(6):373-9.