Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT0NCUUA)

• DOT Name: Oxysterol-binding protein-related protein 6 (OSBPL6)
• Synonyms: ORP-6; OSBP-related protein 6
• Gene Name: OSBPL6
• Related Disease: Alzheimer disease
• UniProt ID: OSBL6_HUMAN
• Pfam ID: PF01237 ; PF15409
• Sequence:
  MSSDEKGISPAHKTSTPTHRSASSSTSSQRDSRQSIHILERTASSSTEPSVSRQLLEPEP
  VPLSKEADSWEIIEGLKIGQTNVQKPDKHEGFMLKKRKWPLKGWHKRFFVLDNGMLKYSK
  APLDIQKGKVHGSIDVGLSVMSIKKKARRIDLDTEEHIYHLKVKSQDWFDAWVSKLRHHR
  LYRQNEIVRSPRDASFHIFPSTSTAESSPAANVSVMDGKMQPNSFPWQSPLPCSNSLPAT
  CTTGQSKVAAWLQDSEEMDRCAEDLAHCQSNLVELSKLLQNLEILQRTQSAPNFTDMQAN
  CVDISKKDKRVTRRWRTKSVSKDTKIQLQVPFSATMSPVRLHSSNPNLCADIEFQTPPSH
  LTDPLESSTDYTKLQEEFCLIAQKVHSLLKSAFNSIAIEKEKLKQMVSEQDHSKGHSTQM
  ARLRQSLSQALNQNAELRSRLNRIHSESIICDQVVSVNIIPSPDEAGEQIHVSLPLSQQV
  ANESRLSMSESVSEFFDAQEVLLSASSSENEASDDESYISDVSDNISEDNTSVADNISRQ
  ILNGELTGGAFRNGRRACLPAPCPDTSNINLWNILRNNIGKDLSKVSMPVELNEPLNTLQ
  HLCEEMEYSELLDKASETDDPYERMVLVAAFAVSGYCSTYFRAGSKPFNPVLGETYECIR
  EDKGFRFFSEQVSHHPPISACHCESKNFVFWQDIRWKNKFWGKSMEILPVGTLNVMLPKY
  GDYYVWNKVTTCIHNILSGRRWIEHYGEVTIRNTKSSVCICKLTFVKVNYWNSNMNEVQG
  VVIDQEGKAVYRLFGKWHEGLYCGVAPSAKCIWRPGSMPTNYELYYGFTRFAIELNELDP
  VLKDLLPPTDARFRPDQRFLEEGNLEAAASEKQRVEELQRSRRRYMEENNLEHIPKFFKK
  VIDANQREAWVSNDTYWELRKDPGFSKVDSPVLW
• Function: Regulates cellular transport and efflux of cholesterol. Plays a role in phosphatidylinositol-4-phophate (PI4P) turnover at the neuronal membrane. Binds via its PH domain PI4P, phosphatidylinositol-4,5-diphosphate, phosphatidylinositol-3,4,5-triphosphate, and phosphatidic acid. Weakly binds 25-hydroxycholesterol.
• Tissue Specificity: Expressed in brain and striated muscle (at protein level) . Widely expressed . Expressed in skeletal muscle .
• Reactome Pathway: Synthesis of bile acids and bile salts (R-HSA-192105)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Alzheimer disease	DISF8S70	Strong	Genetic Variation	[1]

4 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 Oxysterol-binding protein-related protein 6 (OSBPL6).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the methylation of Oxysterol-binding protein-related protein 6 (OSBPL6).	[3]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Oxysterol-binding protein-related protein 6 (OSBPL6).	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Oxysterol-binding protein-related protein 6 (OSBPL6).	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Oxysterol-binding protein-related protein 6 (OSBPL6).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Oxysterol-binding protein-related protein 6 (OSBPL6).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Oxysterol-binding protein-related protein 6 (OSBPL6).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin affects the expression of Oxysterol-binding protein-related protein 6 (OSBPL6).	[7]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Oxysterol-binding protein-related protein 6 (OSBPL6).	[8]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Oxysterol-binding protein-related protein 6 (OSBPL6).	[9]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Oxysterol-binding protein-related protein 6 (OSBPL6).	[7]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Oxysterol-binding protein-related protein 6 (OSBPL6).	[10]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Oxysterol-binding protein-related protein 6 (OSBPL6).	[13]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane increases the expression of Oxysterol-binding protein-related protein 6 (OSBPL6).	[14]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of Oxysterol-binding protein-related protein 6 (OSBPL6).	[15]
GALLICACID	DM6Y3A0	Investigative	GALLICACID increases the expression of Oxysterol-binding protein-related protein 6 (OSBPL6).	[16]
CH-223191	DMMJZYC	Investigative	CH-223191 increases the expression of Oxysterol-binding protein-related protein 6 (OSBPL6).	[17]

References

• [1] Family-based association analyses of imputed genotypes reveal genome-wide significant association of Alzheimer's disease with OSBPL6, PTPRG, and PDCL3.Mol Psychiatry. 2016 Nov;21(11):1608-1612. doi: 10.1038/mp.2015.218. Epub 2016 Feb 2.
• [2] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [3] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [4] 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.
• [5] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [8] Epidermal growth factor receptor signalling in human breast cancer cells operates parallel to estrogen receptor alpha signalling and results in tamoxifen insensitive proliferation. BMC Cancer. 2014 Apr 23;14:283.
• [9] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [10] Dose- and time-dependent transcriptional response of Ishikawa cells exposed to genistein. Toxicol Sci. 2016 May;151(1):71-87.
• [11] 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.
• [12] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [13] 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.
• [14] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.
• [15] Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.
• [16] Gene expression profile analysis of gallic acid-induced cell death process. Sci Rep. 2021 Aug 18;11(1):16743. doi: 10.1038/s41598-021-96174-1.
• [17] Adaptive changes in global gene expression profile of lung carcinoma A549 cells acutely exposed to distinct types of AhR ligands. Toxicol Lett. 2018 Aug;292:162-174.