Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT9HYT7A)

• DOT Name: 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-1 (PLCB1)
• Synonyms: EC 3.1.4.11; PLC-154; Phosphoinositide phospholipase C-beta-1; Phospholipase C-I; PLC-I; Phospholipase C-beta-1; PLC-beta-1
• Gene Name: PLCB1
• Related Disease:
  Infantile spasm
  Developmental and epileptic encephalopathy, 12
  Malignant migrating partial seizures of infancy
  West syndrome
• UniProt ID: PLCB1_HUMAN
• EC Number: 3.1.4.11
• Pfam ID: PF06631 ; PF09279 ; PF17787 ; PF00388 ; PF00387 ; PF08703
• Sequence:
  MAGAQPGVHALQLKPVCVSDSLKKGTKFVKWDDDSTIVTPIILRTDPQGFFFYWTDQNKE
  TELLDLSLVKDARCGRHAKAPKDPKLRELLDVGNIGRLEQRMITVVYGPDLVNISHLNLV
  AFQEEVAKEWTNEVFSLATNLLAQNMSRDAFLEKAYTKLKLQVTPEGRIPLKNIYRLFSA
  DRKRVETALEACSLPSSRNDSIPQEDFTPEVYRVFLNNLCPRPEIDNIFSEFGAKSKPYL
  TVDQMMDFINLKQRDPRLNEILYPPLKQEQVQVLIEKYEPNNSLARKGQISVDGFMRYLS
  GEENGVVSPEKLDLNEDMSQPLSHYFINSSHNTYLTAGQLAGNSSVEMYRQVLLSGCRCV
  ELDCWKGRTAEEEPVITHGFTMTTEISFKEVIEAIAECAFKTSPFPILLSFENHVDSPKQ
  QAKMAEYCRLIFGDALLMEPLEKYPLESGVPLPSPMDLMYKILVKNKKKSHKSSEGSGKK
  KLSEQASNTYSDSSSMFEPSSPGAGEADTESDDDDDDDDCKKSSMDEGTAGSEAMATEEM
  SNLVNYIQPVKFESFEISKKRNKSFEMSSFVETKGLEQLTKSPVEFVEYNKMQLSRIYPK
  GTRVDSSNYMPQLFWNAGCQMVALNFQTMDLAMQINMGMYEYNGKSGYRLKPEFMRRPDK
  HFDPFTEGIVDGIVANTLSVKIISGQFLSDKKVGTYVEVDMFGLPVDTRRKAFKTKTSQG
  NAVNPVWEEEPIVFKKVVLPTLACLRIAVYEEGGKFIGHRILPVQAIRPGYHYICLRNER
  NQPLTLPAVFVYIEVKDYVPDTYADVIEALSNPIRYVNLMEQRAKQLAALTLEDEEEVKK
  EADPGETPSEAPSEARTTPAENGVNHTTTLTPKPPSQALHSQPAPGSVKAPAKTEDLIQS
  VLTEVEAQTIEELKQQKSFVKLQKKHYKEMKDLVKRHHKKTTDLIKEHTTKYNEIQNDYL
  RRRAALEKSAKKDSKKKSEPSSPDHGSSTIEQDLAALDAEMTQKLIDLKDKQQQQLLNLR
  QEQYYSEKYQKREHIKLLIQKLTDVAEECQNNQLKKLKEICEKEKKELKKKMDKKRQEKI
  TEAKSKDKSQMEEEKTEMIRSYIQEVVQYIKRLEEAQSKRQEKLVEKHKEIRQQILDEKP
  KLQVELEQEYQDKFKRLPLEILEFVQEAMKGKISEDSNHGSAPLSLSSDPGKVNHKTPSS
  EELGGDIPGKEFDTPL
• Function: Catalyzes the hydrolysis of 1-phosphatidylinositol 4,5-bisphosphate into diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3) and mediates intracellular signaling downstream of G protein-coupled receptors. Regulates the function of the endothelial barrier.
• KEGG Pathway:
  Inositol phosphate metabolism (hsa00562)
  Metabolic pathways (hsa01100)
  Rap1 sig.ling pathway (hsa04015)
  Calcium sig.ling pathway (hsa04020)
  cGMP-PKG sig.ling pathway (hsa04022)
  Chemokine sig.ling pathway (hsa04062)
  Phosphatidylinositol sig.ling system (hsa04070)
  Sphingolipid sig.ling pathway (hsa04071)
  Phospholipase D sig.ling pathway (hsa04072)
  Adrenergic sig.ling in cardiomyocytes (hsa04261)
  Vascular smooth muscle contraction (hsa04270)
  Wnt sig.ling pathway (hsa04310)
  Apelin sig.ling pathway (hsa04371)
  Gap junction (hsa04540)
  Platelet activation (hsa04611)
  Neutrophil extracellular trap formation (hsa04613)
  NOD-like receptor sig.ling pathway (hsa04621)
  Circadian entrainment (hsa04713)
  Long-term potentiation (hsa04720)
  Retrograde endocan.binoid sig.ling (hsa04723)
  Glutamatergic sy.pse (hsa04724)
  Cholinergic sy.pse (hsa04725)
  Serotonergic sy.pse (hsa04726)
  Dopaminergic sy.pse (hsa04728)
  Long-term depression (hsa04730)
  Taste transduction (hsa04742)
  Inflammatory mediator regulation of TRP channels (hsa04750)
  Insulin secretion (hsa04911)
  GnRH sig.ling pathway (hsa04912)
  Estrogen sig.ling pathway (hsa04915)
  Melanogenesis (hsa04916)
  Thyroid hormone synthesis (hsa04918)
  Thyroid hormone sig.ling pathway (hsa04919)
  Oxytocin sig.ling pathway (hsa04921)
  Glucagon sig.ling pathway (hsa04922)
  Renin secretion (hsa04924)
  Aldosterone synthesis and secretion (hsa04925)
  Relaxin sig.ling pathway (hsa04926)
  Cortisol synthesis and secretion (hsa04927)
  Parathyroid hormone synthesis, secretion and action (hsa04928)
  GnRH secretion (hsa04929)
  AGE-RAGE sig.ling pathway in diabetic complications (hsa04933)
  Cushing syndrome (hsa04934)
  Growth hormone synthesis, secretion and action (hsa04935)
  Endocrine and other factor-regulated calcium reabsorption (hsa04961)
  Salivary secretion (hsa04970)
  Gastric acid secretion (hsa04971)
  Pancreatic secretion (hsa04972)
  Carbohydrate digestion and absorption (hsa04973)
  Alzheimer disease (hsa05010)
  Huntington disease (hsa05016)
  Spinocerebellar ataxia (hsa05017)
  Pathways of neurodegeneration - multiple diseases (hsa05022)
  Shigellosis (hsa05131)
  Chagas disease (hsa05142)
  African trypanosomiasis (hsa05143)
  Amoebiasis (hsa05146)
  Human cytomegalovirus infection (hsa05163)
  Pathways in cancer (hsa05200)
  Diabetic cardiomyopathy (hsa05415)
  Lipid and atherosclerosis (hsa05417)
• Reactome Pathway:
  Synthesis of IP3 and IP4 in the cytosol (R-HSA-1855204)
  Acetylcholine regulates insulin secretion (R-HSA-399997)
  Ca2+ pathway (R-HSA-4086398)
  G alpha (q) signalling events (R-HSA-416476)
  G beta (R-HSA-418217)
  Fatty Acids bound to GPR40 (FFAR1) regulate insulin secretion (R-HSA-434316)
  Presynaptic function of Kainate receptors (R-HSA-500657)
  PLC beta mediated events (R-HSA-112043)
• BioCyc Pathway: MetaCyc:HS11935-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Infantile spasm	DISZSKDG	Definitive	Autosomal recessive	[1]
Developmental and epileptic encephalopathy, 12	DISDMEN3	Strong	Autosomal recessive	[2]
Malignant migrating partial seizures of infancy	DISF2TRU	Supportive	Autosomal dominant	[3]
West syndrome	DISLIAU9	Supportive	Autosomal dominant	[2]

This DOT Affected the Drug Response of 5 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Irinotecan	DMP6SC2	Approved	1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-1 (PLCB1) increases the Drug toxicity ADR of Irinotecan.	[24]
Gentamicin	DMKINJO	Approved	1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-1 (PLCB1) increases the Drug toxicity ADR of Gentamicin.	[25]
Amikacin	DM5PDRB	Approved	1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-1 (PLCB1) increases the Drug toxicity ADR of Amikacin.	[25]
Tobramycin	DMUI0CH	Approved	1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-1 (PLCB1) increases the Drug toxicity ADR of Tobramycin.	[25]
Dibekacin	DMTX0PZ	Phase 4	1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-1 (PLCB1) increases the Drug toxicity ADR of Dibekacin.	[25]

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 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-1 (PLCB1).	[4]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-1 (PLCB1).	[18]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-1 (PLCB1).	[19]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-1 (PLCB1).	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-1 (PLCB1).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-1 (PLCB1).	[6]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-1 (PLCB1).	[7]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-1 (PLCB1).	[8]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-1 (PLCB1).	[9]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-1 (PLCB1).	[10]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-1 (PLCB1).	[11]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-1 (PLCB1).	[12]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-1 (PLCB1).	[13]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol increases the expression of 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-1 (PLCB1).	[14]
Amphotericin B	DMTAJQE	Approved	Amphotericin B increases the expression of 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-1 (PLCB1).	[15]
Azacitidine	DMTA5OE	Approved	Azacitidine increases the expression of 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-1 (PLCB1).	[16]
Methamphetamine	DMPM4SK	Approved	Methamphetamine increases the expression of 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-1 (PLCB1).	[17]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-1 (PLCB1).	[14]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-1 (PLCB1).	[21]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-1 (PLCB1).	[22]
Glyphosate	DM0AFY7	Investigative	Glyphosate decreases the expression of 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-1 (PLCB1).	[23]

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] Phospholipase C beta 1 deficiency is associated with early-onset epileptic encephalopathy. Brain. 2010 Oct;133(10):2964-70. doi: 10.1093/brain/awq238. Epub 2010 Sep 9.
• [3] Homozygous PLCB1 deletion associated with malignant migrating partial seizures in infancy. Epilepsia. 2012 Aug;53(8):e146-50. doi: 10.1111/j.1528-1167.2012.03538.x. Epub 2012 Jun 12.
• [4] 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.
• [5] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [6] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [7] 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.
• [8] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [9] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [10] 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.
• [11] 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.
• [12] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [13] Unique transcriptome, pathways, and networks in the human endometrial fibroblast response to progesterone in endometriosis. Biol Reprod. 2011 Apr;84(4):801-15.
• [14] Gene expression profiling in Ishikawa cells: a fingerprint for estrogen active compounds. Toxicol Appl Pharmacol. 2009 Apr 1;236(1):85-96.
• [15] Differential expression of microRNAs and their predicted targets in renal cells exposed to amphotericin B and its complex with copper (II) ions. Toxicol Mech Methods. 2017 Sep;27(7):537-543. doi: 10.1080/15376516.2017.1333554. Epub 2017 Jun 8.
• [16] Reduction of phosphoinositide-phospholipase C beta1 methylation predicts the responsiveness to azacitidine in high-risk MDS. Proc Natl Acad Sci U S A. 2009 Sep 29;106(39):16811-6. doi: 10.1073/pnas.0907109106. Epub 2009 Sep 10.
• [17] Inhibition of PLC1 signaling pathway regulates methamphetamine self-administration and neurotoxicity in rats. Food Chem Toxicol. 2021 Mar;149:111970. doi: 10.1016/j.fct.2021.111970. Epub 2021 Jan 7.
• [18] 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.
• [19] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [20] 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.
• [21] 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.
• [22] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [23] Glyphosate-based herbicides at low doses affect canonical pathways in estrogen positive and negative breast cancer cell lines. PLoS One. 2019 Jul 11;14(7):e0219610. doi: 10.1371/journal.pone.0219610. eCollection 2019.
• [24] A genome-wide association study for irinotecan-related severe toxicities in patients with advanced non-small-cell lung cancer. Pharmacogenomics J. 2013 Oct;13(5):417-22. doi: 10.1038/tpj.2012.24. Epub 2012 Jun 5.
• [25] ADReCS-Target: target profiles for aiding drug safety research and application. Nucleic Acids Res. 2018 Jan 4;46(D1):D911-D917. doi: 10.1093/nar/gkx899.