Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTYZI6JB)

• DOT Name: 15-hydroxyprostaglandin dehydrogenase (HPGD)
• Synonyms: 15-PGDH; EC 1.1.1.141; Eicosanoid/docosanoid dehydrogenase ; EC 1.1.1.-, EC 1.1.1.232; Prostaglandin dehydrogenase 1; Short chain dehydrogenase/reductase family 36C member 1
• Gene Name: HPGD
• Related Disease:
  Hypertrophic osteoarthropathy, primary, autosomal recessive, 1
  Cranio-osteoarthropathy
  Isolated congenital digital clubbing
  Obsolete pachydermoperiostosis
• UniProt ID: PGDH_HUMAN
• PDB ID: 2GDZ; 8CVN; 8CWL; 8FD8
• EC Number: 1.1.1.-; 1.1.1.141; 1.1.1.232
• Pfam ID: PF00106
• Sequence:
  MHVNGKVALVTGAAQGIGRAFAEALLLKGAKVALVDWNLEAGVQCKAALDEQFEPQKTLF
  IQCDVADQQQLRDTFRKVVDHFGRLDILVNNAGVNNEKNWEKTLQINLVSVISGTYLGLD
  YMSKQNGGEGGIIINMSSLAGLMPVAQQPVYCASKHGIVGFTRSAALAANLMNSGVRLNA
  ICPGFVNTAILESIEKEENMGQYIEYKDHIKDMIKYYGILDPPLIANGLITLIEDDALNG
  AIMKITTSKGIHFQDYDTTPFQAKTQ
• Function: Catalyzes the NAD-dependent dehydrogenation (oxidation) of a broad array of hydroxylated polyunsaturated fatty acids (mainly eicosanoids and docosanoids, including prostaglandins, lipoxins and resolvins), yielding their corresponding keto (oxo) metabolites. Decreases the levels of the pro-proliferative prostaglandins such as prostaglandin E2 (whose activity is increased in cancer because of an increase in the expression of cyclooxygenase 2) and generates oxo-fatty acid products that can profoundly influence cell function by abrogating pro-inflammatory cytokine expression. Converts resolvins E1, D1 and D2 to their oxo products, which represents a mode of resolvin inactivation. Resolvin E1 plays important roles during the resolution phase of acute inflammation, while resolvins D1 and D2 have a unique role in obesity-induced adipose inflammation.
• Tissue Specificity: Detected in colon epithelium (at protein level).
• KEGG Pathway:
  Arachidonic acid metabolism (hsa00590)
  Transcriptio.l misregulation in cancer (hsa05202)
• Reactome Pathway:
  Synthesis of Prostaglandins (PG) and Thromboxanes (TX) (R-HSA-2162123)
  Biosynthesis of D-series resolvins (R-HSA-9018676)
  Biosynthesis of E-series 18(S)-resolvins (R-HSA-9018896)
  Synthesis of Lipoxins (LX) (R-HSA-2142700)
• BioCyc Pathway: MetaCyc:HS09021-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
Hypertrophic osteoarthropathy, primary, autosomal recessive, 1	DIS4HZSS	Definitive	Autosomal recessive	[1]
Cranio-osteoarthropathy	DISJ5ZZB	Supportive	Autosomal recessive	[2]
Isolated congenital digital clubbing	DISZDZ2V	Supportive	Autosomal dominant	[3]
Obsolete pachydermoperiostosis	DIS1R4Y4	Supportive	Autosomal recessive	[2]

This DOT Affected the Regulation of Drug Effects of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Dinoprostone	DMTYOPD	Approved	15-hydroxyprostaglandin dehydrogenase (HPGD) increases the metabolism of Dinoprostone.	[2]
Eicosapentaenoic acid/docosa-hexaenoic acid	DMMUCG4	Approved	15-hydroxyprostaglandin dehydrogenase (HPGD) affects the metabolism of Eicosapentaenoic acid/docosa-hexaenoic acid.	[27]

33 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 15-hydroxyprostaglandin dehydrogenase (HPGD).	[4]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of 15-hydroxyprostaglandin dehydrogenase (HPGD).	[5]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of 15-hydroxyprostaglandin dehydrogenase (HPGD).	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of 15-hydroxyprostaglandin dehydrogenase (HPGD).	[7]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of 15-hydroxyprostaglandin dehydrogenase (HPGD).	[5]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of 15-hydroxyprostaglandin dehydrogenase (HPGD).	[8]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of 15-hydroxyprostaglandin dehydrogenase (HPGD).	[9]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of 15-hydroxyprostaglandin dehydrogenase (HPGD).	[9]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of 15-hydroxyprostaglandin dehydrogenase (HPGD).	[10]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of 15-hydroxyprostaglandin dehydrogenase (HPGD).	[11]
Diclofenac	DMPIHLS	Approved	Diclofenac increases the expression of 15-hydroxyprostaglandin dehydrogenase (HPGD).	[12]
Indomethacin	DMSC4A7	Approved	Indomethacin increases the expression of 15-hydroxyprostaglandin dehydrogenase (HPGD).	[12]
Mifepristone	DMGZQEF	Approved	Mifepristone decreases the expression of 15-hydroxyprostaglandin dehydrogenase (HPGD).	[14]
Ibuprofen	DM8VCBE	Approved	Ibuprofen increases the expression of 15-hydroxyprostaglandin dehydrogenase (HPGD).	[12]
Rofecoxib	DM3P5DA	Approved	Rofecoxib decreases the expression of 15-hydroxyprostaglandin dehydrogenase (HPGD).	[15]
Testosterone Undecanoate	DMZO10Y	Approved	Testosterone Undecanoate increases the expression of 15-hydroxyprostaglandin dehydrogenase (HPGD).	[16]
Flurbiprofen	DMGN4BY	Approved	Flurbiprofen increases the expression of 15-hydroxyprostaglandin dehydrogenase (HPGD).	[12]
Mefenamic acid	DMK7HFI	Approved	Mefenamic acid increases the expression of 15-hydroxyprostaglandin dehydrogenase (HPGD).	[12]
Isoflavone	DM7U58J	Phase 4	Isoflavone affects the expression of 15-hydroxyprostaglandin dehydrogenase (HPGD).	[17]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of 15-hydroxyprostaglandin dehydrogenase (HPGD).	[18]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene affects the expression of 15-hydroxyprostaglandin dehydrogenase (HPGD).	[19]
EXISULIND	DMBY56U	Phase 3	EXISULIND increases the expression of 15-hydroxyprostaglandin dehydrogenase (HPGD).	[12]
Belinostat	DM6OC53	Phase 2	Belinostat increases the expression of 15-hydroxyprostaglandin dehydrogenase (HPGD).	[18]
phorbol 12-myristate 13-acetate	DMJWD62	Phase 2	phorbol 12-myristate 13-acetate increases the expression of 15-hydroxyprostaglandin dehydrogenase (HPGD).	[20]
16,16-dimethyl-PGE2	DMNF38S	Phase 2	16,16-dimethyl-PGE2 increases the activity of 15-hydroxyprostaglandin dehydrogenase (HPGD).	[21]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of 15-hydroxyprostaglandin dehydrogenase (HPGD).	[22]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of 15-hydroxyprostaglandin dehydrogenase (HPGD).	[23]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of 15-hydroxyprostaglandin dehydrogenase (HPGD).	[24]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of 15-hydroxyprostaglandin dehydrogenase (HPGD).	[13]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of 15-hydroxyprostaglandin dehydrogenase (HPGD).	[25]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of 15-hydroxyprostaglandin dehydrogenase (HPGD).	[26]
U0126	DM31OGF	Investigative	U0126 increases the activity of 15-hydroxyprostaglandin dehydrogenase (HPGD).	[12]
PD98059	DMZC90M	Investigative	PD98059 increases the activity of 15-hydroxyprostaglandin dehydrogenase (HPGD).	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Azacitidine	DMTA5OE	Approved	Azacitidine decreases the methylation of 15-hydroxyprostaglandin dehydrogenase (HPGD).	[13]

References

• [1] Flexible and scalable diagnostic filtering of genomic variants using G2P with Ensembl VEP. Nat Commun. 2019 May 30;10(1):2373. doi: 10.1038/s41467-019-10016-3.
• [2] Mutations in 15-hydroxyprostaglandin dehydrogenase cause primary hypertrophic osteoarthropathy. Nat Genet. 2008 Jun;40(6):789-93. doi: 10.1038/ng.153. Epub 2008 May 25.
• [3] Mutation in the HPGD gene encoding NAD+ dependent 15-hydroxyprostaglandin dehydrogenase underlies isolated congenital nail clubbing (ICNC). J Med Genet. 2009 Jan;46(1):14-20. doi: 10.1136/jmg.2008.061234. Epub 2008 Sep 19.
• [4] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [5] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [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] Global effects of inorganic arsenic on gene expression profile in human macrophages. Mol Immunol. 2009 Feb;46(4):649-56.
• [9] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [10] The contribution of methotrexate exposure and host factors on transcriptional variance in human liver. Toxicol Sci. 2007 Jun;97(2):582-94.
• [11] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [12] 15-Hydroxyprostaglandin dehydrogenase (15-PGDH) is up-regulated by flurbiprofen and other non-steroidal anti-inflammatory drugs in human colon cancer HT29 cells. Arch Biochem Biophys. 2009 Jul 15;487(2):139-45. doi: 10.1016/j.abb.2009.05.017. Epub 2009 Jun 6.
• [13] 15-hydroxyprostaglandin dehydrogenase is down-regulated in gastric cancer. Clin Cancer Res. 2009 Jul 15;15(14):4572-80. doi: 10.1158/1078-0432.CCR-08-2518. Epub 2009 Jul 7.
• [14] Mifepristone induced progesterone withdrawal reveals novel regulatory pathways in human endometrium. Mol Hum Reprod. 2007 Sep;13(9):641-54.
• [15] Rofecoxib modulates multiple gene expression pathways in a clinical model of acute inflammatory pain. Pain. 2007 Mar;128(1-2):136-47.
• [16] Levonorgestrel enhances spermatogenesis suppression by testosterone with greater alteration in testicular gene expression in men. Biol Reprod. 2009 Mar;80(3):484-92.
• [17] Soy isoflavones alter expression of genes associated with cancer progression, including interleukin-8, in androgen-independent PC-3 human prostate cancer cells. J Nutr. 2006 Jan;136(1):75-82.
• [18] 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.
• [19] Differential modulation of PI3-kinase/Akt pathway during all-trans retinoic acid- and Am80-induced HL-60 cell differentiation revealed by DNA microarray analysis. Biochem Pharmacol. 2004 Dec 1;68(11):2177-86.
• [20] Indomethacin increases 15-PGDH mRNA expression in HL60 cells differentiated by PMA. Prostaglandins Leukot Essent Fatty Acids. 2001 Feb;64(2):87-93. doi: 10.1054/plef.2001.0246.
• [21] Tumor growth inhibition by indomethacin in a mouse model of human medullary thyroid cancer: implication of cyclooxygenases and 15-hydroxyprostaglandin dehydrogenase. Endocrinology. 2004 May;145(5):2561-71. doi: 10.1210/en.2003-0915. Epub 2004 Jan 21.
• [22] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [23] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [24] Environmental pollutant induced cellular injury is reflected in exosomes from placental explants. Placenta. 2020 Jan 1;89:42-49. doi: 10.1016/j.placenta.2019.10.008. Epub 2019 Oct 17.
• [25] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [26] 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.
• [27] 15-Hydroxyprostaglandin dehydrogenase generation of electrophilic lipid signaling mediators from hydroxy -3 fatty acids. J Biol Chem. 2015 Feb 27;290(9):5868-80. doi: 10.1074/jbc.M114.635151. Epub 2015 Jan 12.