Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT6Z1L2E)

• DOT Name: 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase eta-1 (PLCH1)
• Synonyms: EC 3.1.4.11; Phosphoinositide phospholipase C-eta-1; Phospholipase C-eta-1; PLC-eta-1; Phospholipase C-like protein 3; PLC-L3
• Gene Name: PLCH1
• Related Disease:
  Adenocarcinoma
  Lung cancer
  Lung carcinoma
  Non-small-cell lung cancer
  Squamous cell carcinoma
  Colon cancer
  Colorectal adenocarcinoma
  Colorectal cancer
  Colorectal cancer, susceptibility to, 1
  Colorectal cancer, susceptibility to, 10
  Colorectal cancer, susceptibility to, 12
  Colorectal carcinoma
  Colorectal neoplasm
  Holoprosencephaly 14
• UniProt ID: PLCH1_HUMAN
• EC Number: 3.1.4.11
• Pfam ID: PF00168 ; PF09279 ; PF16457 ; PF00388 ; PF00387
• Sequence:
  MADLEVYKNLSPEKVERCMSVMQSGTQMIKLKRGTKGLVRLFYLDEHRTRLRWRPSRKSE
  KAKILIDSIYKVTEGRQSEIFHRQAEGNFDPSCCFTIYHGNHMESLDLITSNPEEARTWI
  TGLKYLMAGISDEDSLAKRQRTHDQWVKQTFEEADKNGDGLLNIEEIHQLMHKLNVNLPR
  RKVRQMFQEADTDENQGTLTFEEFCVFYKMMSLRRDLYLLLLSYSDKKDHLTVEELAQFL
  KVEQKMNNVTTDYCLDIIKKFEVSEENKVKNVLGIEGFTNFMRSPACDIFNPLHHEVYQD
  MDQPLCNYYIASSHNTYLTGDQLLSQSKVDMYARVLQEGCRCVEVDCWDGPDGEPVVHHG
  YTLTSKILFRDVVETINKHAFVKNEFPVILSIENHCSIQQQRKIAQYLKGIFGDKLDLSS
  VDTGECKQLPSPQSLKGKILVKGKKLPYHLGDDAEEGEVSDEDSADEIEDECKFKLHYSN
  GTTEHQVESFIRKKLESLLKESQIRDKEDPDSFTVRALLKATHEGLNAHLKQSPDVKESG
  KKSHGRSLMTNFGKHKKTTKSRSKSYSTDDEEDTQQSTGKEGGQLYRLGRRRKTMKLCRE
  LSDLVVYTNSVAAQDIVDDGTTGNVLSFSETRAHQVVQQKSEQFMIYNQKQLTRIYPSAY
  RIDSSNFNPLPYWNAGCQLVALNYQSEGRMMQLNRAKFKANGNCGYVLKPQQMCKGTFNP
  FSGDPLPANPKKQLILKVISGQQLPKPPDSMFGDRGEIIDPFVEVEIIGLPVDCCKDQTR
  VVDDNGFNPVWEETLTFTVHMPEIALVRFLVWDHDPIGRDFVGQRTVTFSSLVPGYRHVY
  LEGLTEASIFVHITINEIYGKWSPLILNPSYTILHFLGATKNRQLQGLKGLFNKNPRHSS
  SENNSHYVRKRSIGDRILRRTASAPAKGRKKSKMGFQEMVEIKDSVSEATRDQDGVLRRT
  TRSLQARPVSMPVDRNLLGALSLPVSETAKDIEGKENSLAEDKDGRRKGKASIKDPHFLN
  FNKKLSSSSSALLHKDTSQGDTIVSTAHMSVTGEQLGMSSPRGGRTTSNATSNCQENPCP
  SKSLSPKQHLAPDPVVNPTQDLHGVKIKEKGNPEDFVEGKSILSGSVLSHSNLEIKNLEG
  NRGKGRAATSFSLSDVSMLCSDIPDLHSTAILQESVISHLIDNVTLTNENEPGSSISALI
  GQFDETNNQALTVVSHLHNTSVMSGHCPLPSLGLKMPIKHGFCKGKSKSSFLCSSPELIA
  LSSSETTKHATNTVYETTCTPISKTKPDDDLSSKAKTAALESNLPGSPNTSRGWLPKSPT
  KGEDWETLKSCSPASSPDLTLEDVIADPTLCFNSGESSLVEIDGESENLSLTTCEYRREG
  TSQLASPLKLKYNQGVVEHFQRGLRNGYCKETLRPSVPEIFNNIQDVKTQSISYLAYQGA
  GFVHNHFSDSDAKMFQTCVPQQSSAQDMHVPVPKQLAHLPLPALKLPSPCKSKSLGDLTS
  EDIACNFESKYQCISKSFVTTGIRDKKGVTVKTKSLEPIDALTEQLRKLVSFDQEDNCQV
  LYSKQDANQLPRALVRKLSSRSQSRVRNIASRAKEKQEANKQKVPNPSNGAGVVLRNKPS
  APTPAVNRHSTGSYIAGYLKNTKGGGLEGRGIPEGACTALHYGHVDQFCSDNSVLQTEPS
  SDDKPEIYFLLRL
• Function: The production of the second messenger molecules diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3) is mediated by calcium-activated phosphatidylinositol-specific phospholipase C enzymes.
• Tissue Specificity: Expressed in brain and to a lower extent in lung. In brain, it is found in cerebrum, cerebellum and spinal cord. In embryo expressed in the notochord, developing spinal cord (in a ventral to dorsal gradient), dorsal root ganglia, cerebellum and dermatomyosome.
• KEGG Pathway:
  Inositol phosphate metabolism (hsa00562)
  Metabolic pathways (hsa01100)
• Reactome Pathway: Synthesis of IP3 and IP4 in the cytosol (R-HSA-1855204)

Molecular Interaction Atlas (MIA) of This DOT

14 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adenocarcinoma	DIS3IHTY	Definitive	Genetic Variation	[1]
Lung cancer	DISCM4YA	Definitive	Genetic Variation	[1]
Lung carcinoma	DISTR26C	Definitive	Genetic Variation	[1]
Non-small-cell lung cancer	DIS5Y6R9	Definitive	Genetic Variation	[1]
Squamous cell carcinoma	DISQVIFL	Definitive	Genetic Variation	[1]
Colon cancer	DISVC52G	Strong	Genetic Variation	[2]
Colorectal adenocarcinoma	DISPQOUB	Strong	Genetic Variation	[2]
Colorectal cancer	DISNH7P9	Strong	Genetic Variation	[2]
Colorectal cancer, susceptibility to, 1	DISZ794C	Strong	Genetic Variation	[2]
Colorectal cancer, susceptibility to, 10	DISQXMYM	Strong	Genetic Variation	[2]
Colorectal cancer, susceptibility to, 12	DIS4FXJX	Strong	Genetic Variation	[2]
Colorectal carcinoma	DIS5PYL0	Strong	Genetic Variation	[2]
Colorectal neoplasm	DISR1UCN	Strong	Genetic Variation	[2]
Holoprosencephaly 14	DIS30DT4	Strong	Autosomal recessive	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase eta-1 (PLCH1).	[4]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase eta-1 (PLCH1).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase eta-1 (PLCH1).	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase eta-1 (PLCH1).	[5]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase eta-1 (PLCH1).	[6]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase eta-1 (PLCH1).	[7]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase eta-1 (PLCH1).	[7]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase eta-1 (PLCH1).	[8]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase eta-1 (PLCH1).	[9]
Cytarabine	DMZD5QR	Approved	Cytarabine increases the expression of 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase eta-1 (PLCH1).	[10]
Permethrin	DMZ0Q1G	Approved	Permethrin increases the expression of 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase eta-1 (PLCH1).	[11]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase eta-1 (PLCH1).	[12]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase eta-1 (PLCH1).	[13]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase eta-1 (PLCH1).	[16]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase eta-1 (PLCH1).	[17]

References

• [1] Association between polymorphisms in COMT, PLCH1, and CYP17A1, and non-small-cell lung cancer risk in Chinese nonsmokers.Clin Lung Cancer. 2013 Jan;14(1):45-9. doi: 10.1016/j.cllc.2012.04.004. Epub 2012 Jun 1.
• [2] GWAS identifies two novel colorectal cancer loci at 16q24.1 and 20q13.12.Carcinogenesis. 2018 May 3;39(5):652-660. doi: 10.1093/carcin/bgy026.
• [3] Mutations in phospholipase C eta-1 (PLCH1) are associated with holoprosencephaly. J Med Genet. 2022 Apr;59(4):358-365. doi: 10.1136/jmedgenet-2020-107237. Epub 2021 Apr 5.
• [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] 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.
• [6] 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.
• [7] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [8] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [9] Effects of progesterone treatment on expression of genes involved in uterine quiescence. Reprod Sci. 2011 Aug;18(8):781-97.
• [10] 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.
• [11] Exposure to Insecticides Modifies Gene Expression and DNA Methylation in Hematopoietic Tissues In Vitro. Int J Mol Sci. 2023 Mar 26;24(7):6259. doi: 10.3390/ijms24076259.
• [12] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [13] 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.
• [14] 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.
• [15] 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.
• [16] 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.
• [17] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.