Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTMAR351)

• DOT Name: Prostaglandin reductase 1 (PTGR1)
• Synonyms: PRG-1; 15-oxoprostaglandin 13-reductase; EC 1.3.1.48; Dithiolethione-inducible gene 1 protein; D3T-inducible gene 1 protein; DIG-1; Leukotriene B4 12-hydroxydehydrogenase; NAD(P)H-dependent alkenal/one oxidoreductase; EC 1.3.1.74
• Gene Name: PTGR1
• UniProt ID: PTGR1_HUMAN
• PDB ID: 1ZSV; 2Y05
• EC Number: 1.3.1.48; 1.3.1.74
• Pfam ID: PF16884 ; PF00107
• Sequence:
  MVRTKTWTLKKHFVGYPTNSDFELKTAELPPLKNGEVLLEALFLTVDPYMRVAAKRLKEG
  DTMMGQQVAKVVESKNVALPKGTIVLASPGWTTHSISDGKDLEKLLTEWPDTIPLSLALG
  TVGMPGLTAYFGLLEICGVKGGETVMVNAAAGAVGSVVGQIAKLKGCKVVGAVGSDEKVA
  YLQKLGFDVVFNYKTVESLEETLKKASPDGYDCYFDNVGGEFSNTVIGQMKKFGRIAICG
  AISTYNRTGPLPPGPPPEIVIYQELRMEAFVVYRWQGDARQKALKDLLKWVLEGKIQYKE
  YIIEGFENMPAAFMGMLKGDNLGKTIVKA
• Function: NAD(P)H-dependent oxidoreductase involved in metabolic inactivation of pro- and anti-inflammatory eicosanoids: prostaglandins (PG), leukotrienes (LT) and lipoxins (LX). Catalyzes with high efficiency the reduction of the 13,14 double bond of 15-oxoPGs, including 15-oxo-PGE1, 15-oxo-PGE2, 15-oxo-PGF1-alpha and 15-oxo-PGF2-alpha. Catalyzes with lower efficiency the oxidation of the hydroxyl group at C12 of LTB4 and its derivatives, converting them into biologically less active 12-oxo-LTB4 metabolites. Reduces 15-oxo-LXA4 to 13,14 dihydro-15-oxo-LXA4, enhancing neutrophil recruitment at the inflammatory site. May play a role in metabolic detoxification of alkenals and ketones. Reduces alpha,beta-unsaturated alkenals and ketones, particularly those with medium-chain length, showing highest affinity toward (2E)-decenal and (3E)-3-nonen-2-one. May inactivate 4-hydroxy-2-nonenal, a cytotoxic lipid constituent of oxidized low-density lipoprotein particles.
• Tissue Specificity: High expression in the kidney, liver, and intestine but not in leukocytes.
• KEGG Pathway: Arachidonic acid metabolism (hsa00590)
• Reactome Pathway:
  Synthesis of Lipoxins (LX) (R-HSA-2142700)
  Synthesis of Leukotrienes (LT) and Eoxins (EX) (R-HSA-2142691)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Regulation of Drug Effects of 3 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaldehyde	DMJFKG4	Investigative	Prostaglandin reductase 1 (PTGR1) increases the metabolism of Acetaldehyde.	[17]
13,14-dihydro-15-keto-PGF2alpha	DMNT1XI	Investigative	Prostaglandin reductase 1 (PTGR1) increases the abundance of 13,14-dihydro-15-keto-PGF2alpha.	[17]
PGF1alpha	DMUPWQT	Investigative	Prostaglandin reductase 1 (PTGR1) increases the metabolism of PGF1alpha.	[17]

This DOT Affected the Biotransformations of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
(E)-10-nitrooctadec-9-enoic acid	DMTF7JA	Investigative	Prostaglandin reductase 1 (PTGR1) increases the reduction of (E)-10-nitrooctadec-9-enoic acid.	[30]

45 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 Prostaglandin reductase 1 (PTGR1).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Prostaglandin reductase 1 (PTGR1).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Prostaglandin reductase 1 (PTGR1).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Prostaglandin reductase 1 (PTGR1).	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Prostaglandin reductase 1 (PTGR1).	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin affects the expression of Prostaglandin reductase 1 (PTGR1).	[6]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Prostaglandin reductase 1 (PTGR1).	[7]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Prostaglandin reductase 1 (PTGR1).	[8]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Prostaglandin reductase 1 (PTGR1).	[9]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Prostaglandin reductase 1 (PTGR1).	[10]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Prostaglandin reductase 1 (PTGR1).	[11]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Prostaglandin reductase 1 (PTGR1).	[12]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Prostaglandin reductase 1 (PTGR1).	[13]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Prostaglandin reductase 1 (PTGR1).	[6]
Menadione	DMSJDTY	Approved	Menadione increases the expression of Prostaglandin reductase 1 (PTGR1).	[11]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil increases the expression of Prostaglandin reductase 1 (PTGR1).	[14]
Cannabidiol	DM0659E	Approved	Cannabidiol increases the expression of Prostaglandin reductase 1 (PTGR1).	[15]
Azathioprine	DMMZSXQ	Approved	Azathioprine increases the expression of Prostaglandin reductase 1 (PTGR1).	[16]
Diclofenac	DMPIHLS	Approved	Diclofenac decreases the activity of Prostaglandin reductase 1 (PTGR1).	[17]
Sodium lauryl sulfate	DMLJ634	Approved	Sodium lauryl sulfate increases the expression of Prostaglandin reductase 1 (PTGR1).	[18]
Indomethacin	DMSC4A7	Approved	Indomethacin decreases the activity of Prostaglandin reductase 1 (PTGR1).	[17]
Ibuprofen	DM8VCBE	Approved	Ibuprofen affects the activity of Prostaglandin reductase 1 (PTGR1).	[17]
Ampicillin	DMHWE7P	Approved	Ampicillin decreases the expression of Prostaglandin reductase 1 (PTGR1).	[8]
Benzoic acid	DMKB9FI	Approved	Benzoic acid increases the expression of Prostaglandin reductase 1 (PTGR1).	[18]
Gamolenic acid	DMQN30Z	Approved	Gamolenic acid increases the expression of Prostaglandin reductase 1 (PTGR1).	[19]
Niflumic acid	DMJ3I1Q	Approved	Niflumic acid decreases the activity of Prostaglandin reductase 1 (PTGR1).	[17]
Fenoprofen	DML5VQ0	Approved	Fenoprofen affects the activity of Prostaglandin reductase 1 (PTGR1).	[17]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Prostaglandin reductase 1 (PTGR1).	[20]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of Prostaglandin reductase 1 (PTGR1).	[21]
DNCB	DMDTVYC	Phase 2	DNCB increases the expression of Prostaglandin reductase 1 (PTGR1).	[18]
Disulfiram	DMCL2OK	Phase 2 Trial	Disulfiram increases the expression of Prostaglandin reductase 1 (PTGR1).	[18]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Prostaglandin reductase 1 (PTGR1).	[22]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Prostaglandin reductase 1 (PTGR1).	[23]
Eugenol	DM7US1H	Patented	Eugenol increases the expression of Prostaglandin reductase 1 (PTGR1).	[18]
Nimesulide	DMR1NMD	Terminated	Nimesulide affects the activity of Prostaglandin reductase 1 (PTGR1).	[17]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Prostaglandin reductase 1 (PTGR1).	[24]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Prostaglandin reductase 1 (PTGR1).	[12]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Prostaglandin reductase 1 (PTGR1).	[25]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane increases the expression of Prostaglandin reductase 1 (PTGR1).	[26]
chloropicrin	DMSGBQA	Investigative	chloropicrin increases the expression of Prostaglandin reductase 1 (PTGR1).	[27]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of Prostaglandin reductase 1 (PTGR1).	[28]
Resorcinol	DMM37C0	Investigative	Resorcinol increases the expression of Prostaglandin reductase 1 (PTGR1).	[16]
Lead acetate	DML0GZ2	Investigative	Lead acetate increases the expression of Prostaglandin reductase 1 (PTGR1).	[29]
methyl salicylate	DMKCG8H	Investigative	methyl salicylate increases the expression of Prostaglandin reductase 1 (PTGR1).	[18]
2-Propanol, Isopropanol	DML5O0H	Investigative	2-Propanol, Isopropanol increases the expression of Prostaglandin reductase 1 (PTGR1).	[18]

References

• [1] The neuroprotective action of the mood stabilizing drugs lithium chloride and sodium valproate is mediated through the up-regulation of the homeodomain protein Six1. Toxicol Appl Pharmacol. 2009 Feb 15;235(1):124-34.
• [2] 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.
• [3] 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.
• [4] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [5] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [6] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [7] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [8] 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.
• [9] 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.
• [10] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [11] Time series analysis of oxidative stress response patterns in HepG2: a toxicogenomics approach. Toxicology. 2013 Apr 5;306:24-34.
• [12] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [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] Proteomic analysis of antiproliferative effects by treatment of 5-fluorouracil in cervical cancer cells. DNA Cell Biol. 2004 Nov;23(11):769-76.
• [15] Cannabidiol induces antioxidant pathways in keratinocytes by targeting BACH1. Redox Biol. 2020 Jan;28:101321. doi: 10.1016/j.redox.2019.101321. Epub 2019 Sep 5.
• [16] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.
• [17] Human prostaglandin reductase 1 (PGR1): Substrate specificity, inhibitor analysis and site-directed mutagenesis. Chem Biol Interact. 2015 Jun 5;234:105-13.
• [18] Keratinocyte gene expression profiles discriminate sensitizing and irritating compounds. Toxicol Sci. 2010 Sep;117(1):81-9.
• [19] Antineoplastic effects of gamma linolenic Acid on hepatocellular carcinoma cell lines. J Clin Biochem Nutr. 2010 Jul;47(1):81-90.
• [20] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [21] Identification by automated screening of a small molecule that selectively eliminates neural stem cells derived from hESCs but not dopamine neurons. PLoS One. 2009 Sep 23;4(9):e7155.
• [22] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [23] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [24] Alternatives for the worse: Molecular insights into adverse effects of bisphenol a and substitutes during human adipocyte differentiation. Environ Int. 2021 Nov;156:106730. doi: 10.1016/j.envint.2021.106730. Epub 2021 Jun 27.
• [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] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.
• [28] Microphysiological system modeling of ochratoxin A-associated nephrotoxicity. Toxicology. 2020 Nov;444:152582. doi: 10.1016/j.tox.2020.152582. Epub 2020 Sep 6.
• [29] Analysis of lead toxicity in human cells. BMC Genomics. 2012 Jul 27;13:344.
• [30] Modulation of nitro-fatty acid signaling: prostaglandin reductase-1 is a nitroalkene reductase. J Biol Chem. 2013 Aug 30;288(35):25626-25637. doi: 10.1074/jbc.M113.486282. Epub 2013 Jul 22.