Details of Drug Off-Target (DOT)

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

• DOT Name: Lipase member H (LIPH)
• Synonyms: LIPH; EC 3.1.1.-; LPD lipase-related protein; Membrane-associated phosphatidic acid-selective phospholipase A1-alpha; mPA-PLA1 alpha; Phospholipase A1 member B
• Gene Name: LIPH
• Related Disease:
  Adenocarcinoma
  Lung adenocarcinoma
  Lung cancer
  Lung carcinoma
  Minimally invasive lung adenocarcinoma
  Advanced cancer
  Alopecia
  Hypercholesterolemia, familial, 4
  Hypotrichosis 7
  Hypotrichosis 8
  Thyroid gland papillary carcinoma
  Hypotrichosis simplex
  Isolated familial wooly hair disorder
  Hypotrichosis 13
• UniProt ID: LIPH_HUMAN
• EC Number: 3.1.1.-
• Pfam ID: PF00151
• Sequence:
  MLRFYLFISLLCLSRSDAEETCPSFTRLSFHSAVVGTGLNVRLMLYTRKNLTCAQTINSS
  AFGNLNVTKKTTFIVHGFRPTGSPPVWMDDLVKGLLSVEDMNVVVVDWNRGATTLIYTHA
  SSKTRKVAMVLKEFIDQMLAEGASLDDIYMIGVSLGAHISGFVGEMYDGWLGRITGLDPA
  GPLFNGKPHQDRLDPSDAQFVDVIHSDTDALGYKEPLGNIDFYPNGGLDQPGCPKTILGG
  FQYFKCDHQRSVYLYLSSLRESCTITAYPCDSYQDYRNGKCVSCGTSQKESCPLLGYYAD
  NWKDHLRGKDPPMTKAFFDTAEESPFCMYHYFVDIITWNKNVRRGDITIKLRDKAGNTTE
  SKINHEPTTFQKYHQVSLLARFNQDLDKVAAISLMFSTGSLIGPRYKLRILRMKLRSLAH
  PERPQLCRYDLVLMENVETVFQPILCPELQL
• Function: Hydrolyzes specifically phosphatidic acid (PA) to produce 2-acyl lysophosphatidic acid (LPA; a potent bioactive lipid mediator) and fatty acid. Does not hydrolyze other phospholipids, like phosphatidylserine (PS), phosphatidylcholine (PC) and phosphatidylethanolamine (PE) or triacylglycerol (TG).
• Tissue Specificity: Present in intestine (at protein level). Expressed in colon, prostate, kidney, pancreas, ovary, testis, intestine, lung and pancreas. Expressed at lower level in brain, spleen and heart. In the skin, it is prominently expressed in hair follicles, including the stem cell-rich bulge region and the inner root sheath .
• Reactome Pathway: Synthesis of PA (R-HSA-1483166)

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	Altered Expression	[1]
Lung adenocarcinoma	DISD51WR	Definitive	Altered Expression	[1]
Lung cancer	DISCM4YA	Definitive	Altered Expression	[1]
Lung carcinoma	DISTR26C	Definitive	Altered Expression	[1]
Minimally invasive lung adenocarcinoma	DIS4W83X	Definitive	Altered Expression	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Alopecia	DIS37HU4	Strong	Genetic Variation	[3]
Hypercholesterolemia, familial, 4	DISFLNLI	Strong	Genetic Variation	[4]
Hypotrichosis 7	DISDFBQ5	Strong	Autosomal recessive	[5]
Hypotrichosis 8	DIS2FX7S	Strong	Genetic Variation	[6]
Thyroid gland papillary carcinoma	DIS48YMM	Strong	Altered Expression	[2]
Hypotrichosis simplex	DIS8WHDJ	Supportive	Autosomal dominant	[7]
Isolated familial wooly hair disorder	DISTWYN7	Supportive	Autosomal dominant	[8]
Hypotrichosis 13	DISEECSG	Limited	Genetic Variation	[9]

16 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 Lipase member H (LIPH).	[10]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Lipase member H (LIPH).	[11]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Lipase member H (LIPH).	[12]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Lipase member H (LIPH).	[13]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Lipase member H (LIPH).	[15]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Lipase member H (LIPH).	[16]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil decreases the expression of Lipase member H (LIPH).	[17]
Hydroxyurea	DMOQVU9	Approved	Hydroxyurea decreases the expression of Lipase member H (LIPH).	[18]
2-deoxyglucose	DMIAHVU	Approved	2-deoxyglucose decreases the expression of Lipase member H (LIPH).	[18]
Bleomycin	DMNER5S	Approved	Bleomycin decreases the expression of Lipase member H (LIPH).	[18]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Lipase member H (LIPH).	[19]
GSK2110183	DMZHB37	Phase 2	GSK2110183 increases the expression of Lipase member H (LIPH).	[20]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Lipase member H (LIPH).	[15]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Lipase member H (LIPH).	[21]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Lipase member H (LIPH).	[22]
Glyphosate	DM0AFY7	Investigative	Glyphosate decreases the expression of Lipase member H (LIPH).	[21]

1 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 Lipase member H (LIPH).	[14]

References

• [1] Lipase member H is a novel secreted protein selectively upregulated in human lung adenocarcinomas and bronchioloalveolar carcinomas.Biochem Biophys Res Commun. 2014 Jan 24;443(4):1141-7. doi: 10.1016/j.bbrc.2013.12.106. Epub 2013 Dec 28.
• [2] Lipase member H is a downstream molecular target of hypoxia inducible factor-1 and promotes papillary thyroid carcinoma cell migration in BCPAP and KTC-1 cell lines.Cancer Manag Res. 2019 Jan 22;11:931-941. doi: 10.2147/CMAR.S183355. eCollection 2019.
• [3] Identification of factors contributing to phenotypic divergence via quantitative image analyses of autosomal recessive woolly hair/hypotrichosis with homozygous c.736T>A LIPH mutation.Br J Dermatol. 2017 Jan;176(1):138-144. doi: 10.1111/bjd.14836. Epub 2016 Dec 19.
• [4] Autosomal Recessive Hypotrichosis with Woolly Hair Caused by a Mutation in the Keratin 25 Gene Expressed in Hair Follicles.J Invest Dermatol. 2016 Jun;136(6):1097-1105. doi: 10.1016/j.jid.2016.01.037. Epub 2016 Feb 20.
• [5] A mutation in the lipase H (LIPH) gene underlie autosomal recessive hypotrichosis. Hum Genet. 2007 May;121(3-4):319-25. doi: 10.1007/s00439-007-0344-0. Epub 2007 Feb 27.
• [6] 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.
• [7] A novel deletion mutation in LIPH gene causes autosomal recessive hypotrichosis (LAH2). Clin Genet. 2008 Aug;74(2):184-8. doi: 10.1111/j.1399-0004.2008.01011.x. Epub 2008 Apr 28.
• [8] 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.
• [9] A novel mutation in the Lipase H gene underlies autosomal recessive hypotrichosis and woolly hair.Sci Rep. 2012;2:730. doi: 10.1038/srep00730. Epub 2012 Oct 12.
• [10] Stem cell transcriptome responses and corresponding biomarkers that indicate the transition from adaptive responses to cytotoxicity. Chem Res Toxicol. 2017 Apr 17;30(4):905-922.
• [11] 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.
• [12] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [13] 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.
• [14] 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.
• [15] 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.
• [16] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [17] Cellular response to 5-fluorouracil (5-FU) in 5-FU-resistant colon cancer cell lines during treatment and recovery. Mol Cancer. 2006 May 18;5:20. doi: 10.1186/1476-4598-5-20.
• [18] Development and validation of the TGx-HDACi transcriptomic biomarker to detect histone deacetylase inhibitors in human TK6 cells. Arch Toxicol. 2021 May;95(5):1631-1645. doi: 10.1007/s00204-021-03014-2. Epub 2021 Mar 26.
• [19] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [20] Novel ATP-competitive Akt inhibitor afuresertib suppresses the proliferation of malignant pleural mesothelioma cells. Cancer Med. 2017 Nov;6(11):2646-2659. doi: 10.1002/cam4.1179. Epub 2017 Sep 27.
• [21] Evaluation of estrogen receptor alpha activation by glyphosate-based herbicide constituents. Food Chem Toxicol. 2017 Oct;108(Pt A):30-42.
• [22] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.