Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT4BY3W4)

• DOT Name: Lysophosphatidic acid receptor 6 (LPAR6)
• Synonyms: LPA receptor 6; LPA-6; Oleoyl-L-alpha-lysophosphatidic acid receptor; P2Y purinoceptor 5; P2Y5; Purinergic receptor 5; RB intron encoded G-protein coupled receptor
• Gene Name: LPAR6
• Related Disease:
  Hypotrichosis 8
  Hypotrichosis simplex
  Isolated familial wooly hair disorder
• UniProt ID: LPAR6_HUMAN
• Pfam ID: PF00001
• Sequence:
  MVSVNSSHCFYNDSFKYTLYGCMFSMVFVLGLISNCVAIYIFICVLKVRNETTTYMINLA
  MSDLLFVFTLPFRIFYFTTRNWPFGDLLCKISVMLFYTNMYGSILFLTCISVDRFLAIVY
  PFKSKTLRTKRNAKIVCTGVWLTVIGGSAPAVFVQSTHSQGNNASEACFENFPEATWKTY
  LSRIVIFIEIVGFFIPLILNVTCSSMVLKTLTKPVTLSRSKINKTKVLKMIFVHLIIFCF
  CFVPYNINLILYSLVRTQTFVNCSVVAAVRTMYPITLCIAVSNCCFDPIVYYFTSDTIQN
  SIKMKNWSVRRSDFRFSEVHGAENFIQHNLQTLKSKIFDNESAA
• Function: Binds to oleoyl-L-alpha-lysophosphatidic acid (LPA). Intracellular cAMP is involved in the receptor activation. Important for the maintenance of hair growth and texture.
• Tissue Specificity: Expressed ubiquitously, including in skin and hair follicle cells. Detected in both Henle's and Huxley's layers of the inner root sheath of the hair follicle and in suprabasal layers of the epidermis (at protein level). Expressed at low levels in peripheral blood leukocytes.
• KEGG Pathway:
  Phospholipase D sig.ling pathway (hsa04072)
  Neuroactive ligand-receptor interaction (hsa04080)
  PI3K-Akt sig.ling pathway (hsa04151)
  Pathways in cancer (hsa05200)
• Reactome Pathway:
  P2Y receptors (R-HSA-417957)
  G alpha (q) signalling events (R-HSA-416476)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hypotrichosis 8	DIS2FX7S	Strong	Autosomal recessive	[1]
Hypotrichosis simplex	DIS8WHDJ	Supportive	Autosomal dominant	[2]
Isolated familial wooly hair disorder	DISTWYN7	Supportive	Autosomal dominant	[3]

2 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 Lysophosphatidic acid receptor 6 (LPAR6).	[4]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Lysophosphatidic acid receptor 6 (LPAR6).	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Lysophosphatidic acid receptor 6 (LPAR6).	[5]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Lysophosphatidic acid receptor 6 (LPAR6).	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Lysophosphatidic acid receptor 6 (LPAR6).	[7]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Lysophosphatidic acid receptor 6 (LPAR6).	[8]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Lysophosphatidic acid receptor 6 (LPAR6).	[9]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Lysophosphatidic acid receptor 6 (LPAR6).	[11]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Lysophosphatidic acid receptor 6 (LPAR6).	[12]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Lysophosphatidic acid receptor 6 (LPAR6).	[13]
Marinol	DM70IK5	Approved	Marinol increases the expression of Lysophosphatidic acid receptor 6 (LPAR6).	[14]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil decreases the expression of Lysophosphatidic acid receptor 6 (LPAR6).	[15]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Lysophosphatidic acid receptor 6 (LPAR6).	[12]
Azathioprine	DMMZSXQ	Approved	Azathioprine decreases the expression of Lysophosphatidic acid receptor 6 (LPAR6).	[16]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of Lysophosphatidic acid receptor 6 (LPAR6).	[17]
Gemcitabine	DMSE3I7	Approved	Gemcitabine decreases the expression of Lysophosphatidic acid receptor 6 (LPAR6).	[15]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Lysophosphatidic acid receptor 6 (LPAR6).	[18]
Belinostat	DM6OC53	Phase 2	Belinostat increases the expression of Lysophosphatidic acid receptor 6 (LPAR6).	[12]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Lysophosphatidic acid receptor 6 (LPAR6).	[19]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Lysophosphatidic acid receptor 6 (LPAR6).	[20]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Lysophosphatidic acid receptor 6 (LPAR6).	[21]
QUERCITRIN	DM1DH96	Investigative	QUERCITRIN decreases the expression of Lysophosphatidic acid receptor 6 (LPAR6).	[22]
Resorcinol	DMM37C0	Investigative	Resorcinol increases the expression of Lysophosphatidic acid receptor 6 (LPAR6).	[16]

References

• [1] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [2] Novel mutations in G protein-coupled receptor gene (P2RY5) in families with autosomal recessive hypotrichosis (LAH3). Hum Genet. 2008 Jun;123(5):515-9. doi: 10.1007/s00439-008-0507-7. Epub 2008 May 7.
• [3] Mutations in the LPAR6 and LIPH genes underlie autosomal recessive hypotrichosis/woolly hair in 17 consanguineous families from Pakistan. Clin Exp Dermatol. 2011 Aug;36(6):652-4. doi: 10.1111/j.1365-2230.2011.04014.x. Epub 2011 Mar 21.
• [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] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [6] 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.
• [7] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [8] 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.
• [9] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [10] 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.
• [11] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [12] 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.
• [13] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [14] Single-cell Transcriptome Mapping Identifies Common and Cell-type Specific Genes Affected by Acute Delta9-tetrahydrocannabinol in Humans. Sci Rep. 2020 Feb 26;10(1):3450. doi: 10.1038/s41598-020-59827-1.
• [15] Gene expression profiling of breast cancer cells in response to gemcitabine: NF-kappaB pathway activation as a potential mechanism of resistance. Breast Cancer Res Treat. 2007 Apr;102(2):157-72.
• [16] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.
• [17] Transcriptional profiling of testosterone-regulated genes in the skeletal muscle of human immunodeficiency virus-infected men experiencing weight loss. J Clin Endocrinol Metab. 2007 Jul;92(7):2793-802. doi: 10.1210/jc.2006-2722. Epub 2007 Apr 17.
• [18] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [19] New insights into BaP-induced toxicity: role of major metabolites in transcriptomics and contribution to hepatocarcinogenesis. Arch Toxicol. 2016 Jun;90(6):1449-58.
• [20] Transcriptomic?pathway?and?benchmark dose analysis of Bisphenol A, Bisphenol S, Bisphenol F, and 3,3',5,5'-Tetrabromobisphenol A in H9 human embryonic stem cells. Toxicol In Vitro. 2021 Apr;72:105097. doi: 10.1016/j.tiv.2021.105097. Epub 2021 Jan 18.
• [21] 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.
• [22] Molecular mechanisms of quercitrin-induced apoptosis in non-small cell lung cancer. Arch Med Res. 2014 Aug;45(6):445-54.