Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT8ALXHU)

• DOT Name: Pirin (PIR)
• Synonyms: EC 1.13.11.24; Probable quercetin 2,3-dioxygenase PIR; Probable quercetinase
• Gene Name: PIR
• Related Disease:
  Arthritis
  Acute monocytic leukemia
  Acute myelogenous leukaemia
  Castration-resistant prostate carcinoma
  Chronic obstructive pulmonary disease
  Colitis
  Inflammatory bowel disease
  Melanoma
  Neoplasm
  Promyelocytic leukaemia
  Pulmonary disease
  Breast cancer
  Breast carcinoma
  Advanced cancer
  Contact dermatitis
  Osteoporosis
  Rheumatoid arthritis
• UniProt ID: PIR_HUMAN
• PDB ID: 1J1L; 3ACL; 4ERO; 4EWA; 4EWD; 4EWE; 4GUL; 4HLT; 5JCT; 6H1H; 6H1I; 6N0J; 6N0K
• EC Number: 1.13.11.24
• Pfam ID: PF02678 ; PF05726
• Sequence:
  MGSSKKVTLSVLSREQSEGVGARVRRSIGRPELKNLDPFLLFDEFKGGRPGGFPDHPHRG
  FETVSYLLEGGSMAHEDFCGHTGKMNPGDLQWMTAGRGILHAEMPCSEEPAHGLQLWVNL
  RSSEKMVEPQYQELKSEEIPKPSKDGVTVAVISGEALGIKSKVYTRTPTLYLDFKLDPGA
  KHSQPIPKGWTSFIYTISGDVYIGPDDAQQKIEPHHTAVLGEGDSVQVENKDPKRSHFVL
  IAGEPLREPVIQHGPFVMNTNEEISQAILDFRNAKNGFERAKTWKSKIGN
• Function: Transcriptional coregulator of NF-kappa-B which facilitates binding of NF-kappa-B proteins to target kappa-B genes in a redox-state-dependent manner. May be required for efficient terminal myeloid maturation of hematopoietic cells. Has quercetin 2,3-dioxygenase activity (in vitro).
• Tissue Specificity: Highly expressed in a subset of melanomas. Detected at very low levels in most tissues (at protein level). Expressed in all tissues, with highest level of expression in heart and liver.
• Reactome Pathway: Digestion (R-HSA-8935690)

Molecular Interaction Atlas (MIA) of This DOT

17 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Arthritis	DIST1YEL	Definitive	Genetic Variation	[1]
Acute monocytic leukemia	DIS28NEL	Strong	Altered Expression	[2]
Acute myelogenous leukaemia	DISCSPTN	Strong	Biomarker	[2]
Castration-resistant prostate carcinoma	DISVGAE6	Strong	Altered Expression	[3]
Chronic obstructive pulmonary disease	DISQCIRF	Strong	Biomarker	[4]
Colitis	DISAF7DD	Strong	Biomarker	[5]
Inflammatory bowel disease	DISGN23E	Strong	Biomarker	[5]
Melanoma	DIS1RRCY	Strong	Biomarker	[6]
Neoplasm	DISZKGEW	Strong	Biomarker	[7]
Promyelocytic leukaemia	DISYGG13	Strong	Altered Expression	[2]
Pulmonary disease	DIS6060I	Strong	Biomarker	[4]
Breast cancer	DIS7DPX1	moderate	Biomarker	[7]
Breast carcinoma	DIS2UE88	moderate	Biomarker	[7]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[3]
Contact dermatitis	DISQ3AU0	Limited	Biomarker	[8]
Osteoporosis	DISF2JE0	Limited	Biomarker	[9]
Rheumatoid arthritis	DISTSB4J	Limited	Altered Expression	[10]

This DOT Affected the Drug Response of 3 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Pirin (PIR) affects the response to substance of Doxorubicin.	[40]
Mitomycin	DMH0ZJE	Approved	Pirin (PIR) affects the response to substance of Mitomycin.	[40]
Vinblastine	DM5TVS3	Approved	Pirin (PIR) affects the response to substance of Vinblastine.	[40]

35 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 Pirin (PIR).	[11]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Pirin (PIR).	[12]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Pirin (PIR).	[13]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Pirin (PIR).	[14]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Pirin (PIR).	[15]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Pirin (PIR).	[16]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Pirin (PIR).	[17]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Pirin (PIR).	[18]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Pirin (PIR).	[19]
Marinol	DM70IK5	Approved	Marinol increases the expression of Pirin (PIR).	[20]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Pirin (PIR).	[21]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil decreases the expression of Pirin (PIR).	[22]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Pirin (PIR).	[23]
Bortezomib	DMNO38U	Approved	Bortezomib increases the expression of Pirin (PIR).	[24]
Sodium lauryl sulfate	DMLJ634	Approved	Sodium lauryl sulfate decreases the expression of Pirin (PIR).	[25]
Cidofovir	DMA13GD	Approved	Cidofovir increases the expression of Pirin (PIR).	[21]
Clodronate	DM9Y6X7	Approved	Clodronate increases the expression of Pirin (PIR).	[21]
Alitretinoin	DMME8LH	Approved	Alitretinoin increases the expression of Pirin (PIR).	[13]
Adefovir dipivoxil	DMMAWY1	Approved	Adefovir dipivoxil increases the expression of Pirin (PIR).	[21]
Ampicillin	DMHWE7P	Approved	Ampicillin increases the expression of Pirin (PIR).	[26]
Penicillin V	DMKVOYF	Approved	Penicillin V increases the expression of Pirin (PIR).	[26]
Sulfamethoxazole	DMB08GE	Approved	Sulfamethoxazole increases the expression of Pirin (PIR).	[26]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Pirin (PIR).	[27]
Isoflavone	DM7U58J	Phase 4	Isoflavone increases the expression of Pirin (PIR).	[28]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Pirin (PIR).	[29]
Fenretinide	DMRD5SP	Phase 3	Fenretinide increases the expression of Pirin (PIR).	[30]
Benzylpenicillin	DMS9503	Phase 3	Benzylpenicillin increases the expression of Pirin (PIR).	[26]
DNCB	DMDTVYC	Phase 2	DNCB increases the expression of Pirin (PIR).	[31]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Pirin (PIR).	[33]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Pirin (PIR).	[35]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane increases the expression of Pirin (PIR).	[36]
cinnamaldehyde	DMZDUXG	Investigative	cinnamaldehyde increases the expression of Pirin (PIR).	[37]
all-trans-4-oxo-retinoic acid	DMM2R1N	Investigative	all-trans-4-oxo-retinoic acid increases the expression of Pirin (PIR).	[13]
Lead acetate	DML0GZ2	Investigative	Lead acetate increases the expression of Pirin (PIR).	[38]
N-(3-METHYLBUT-2-EN-1-YL)-9H-PURIN-6-AMINE	DM2D4KY	Investigative	N-(3-METHYLBUT-2-EN-1-YL)-9H-PURIN-6-AMINE increases the expression of Pirin (PIR).	[39]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Pirin (PIR).	[32]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Pirin (PIR).	[34]

References

• [1] Autoimmune arthritis induces paired immunoglobulin-like receptor B expression on CD4(+) Tcells from SKG mice.Eur J Immunol. 2017 Sep;47(9):1457-1467. doi: 10.1002/eji.201646747. Epub 2017 Jul 27.
• [2] Pirin downregulation is a feature of AML and leads to impairment of terminal myeloid differentiation.Leukemia. 2010 Feb;24(2):429-37. doi: 10.1038/leu.2009.247. Epub 2009 Dec 10.
• [3] Pirin: a potential novel therapeutic target for castration-resistant prostate cancer regulated by miR-455-5p.Mol Oncol. 2019 Feb;13(2):322-337. doi: 10.1002/1878-0261.12405. Epub 2018 Dec 21.
• [4] Ambient particulate matter attenuates Sirtuin1 and augments SREBP1-PIR axis to induce human pulmonary fibroblast inflammation: molecular mechanism of microenvironment associated with COPD.Aging (Albany NY). 2019 Jul 12;11(13):4654-4671. doi: 10.18632/aging.102077.
• [5] Induction of PIR-A/B(+) DCs in the in vitro inflammatory condition and their immunoregulatory function.J Gastroenterol. 2018 Oct;53(10):1131-1141. doi: 10.1007/s00535-018-1447-1. Epub 2018 Mar 5.
• [6] A small-molecule inhibitor shows that pirin regulates migration of melanoma cells.Nat Chem Biol. 2010 Sep;6(9):667-73. doi: 10.1038/nchembio.423. Epub 2010 Aug 15.
• [7] PIR promotes tumorigenesis of breast cancer by upregulating cell cycle activator E2F1.Cell Cycle. 2019 Nov;18(21):2914-2927. doi: 10.1080/15384101.2019.1662259. Epub 2019 Sep 10.
• [8] Genes specifically modulated in sensitized skins allow the detection of sensitizers in a reconstructed human skin modelDevelopment of the SENS-IS assay. Toxicol In Vitro. 2015 Jun;29(4):787-802.
• [9] Sex-specific effect of Pirin gene on bone mineral density in a cohort of 4000 Chinese.Bone. 2010 Feb;46(2):543-50. doi: 10.1016/j.bone.2009.09.012. Epub 2009 Sep 18.
• [10] Proteins related to the functions of fibroblast-like synoviocytes identified by proteomic analysis.Clin Exp Rheumatol. 2012 Mar-Apr;30(2):213-21. Epub 2012 Apr 13.
• [11] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [12] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [13] Retinoic acid and its 4-oxo metabolites are functionally active in human skin cells in vitro. J Invest Dermatol. 2005 Jul;125(1):143-53.
• [14] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [15] 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.
• [16] 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.
• [17] Arsenic suppresses gene expression in promyelocytic leukemia cells partly through Sp1 oxidation. Blood. 2005 Jul 1;106(1):304-10.
• [18] 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.
• [19] 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.
• [20] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [21] Transcriptomics hit the target: monitoring of ligand-activated and stress response pathways for chemical testing. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):7-18.
• [22] Dissecting progressive stages of 5-fluorouracil resistance in vitro using RNA expression profiling. Int J Cancer. 2004 Nov 1;112(2):200-12. doi: 10.1002/ijc.20401.
• [23] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [24] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [25] CXCL14 downregulation in human keratinocytes is a potential biomarker for a novel in vitro skin sensitization test. Toxicol Appl Pharmacol. 2020 Jan 1;386:114828. doi: 10.1016/j.taap.2019.114828. Epub 2019 Nov 14.
• [26] Evaluation of the sensitizing potential of antibiotics in vitro using the human cell lines THP-1 and MUTZ-LC and primary monocyte-derived dendritic cells. Toxicol Appl Pharmacol. 2012 Aug 1;262(3):283-92.
• [27] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [28] Soy isoflavones exert differential effects on androgen responsive genes in LNCaP human prostate cancer cells. J Nutr. 2007 Apr;137(4):964-72.
• [29] 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.
• [30] Regulation of lipocalin-2 gene by the cancer chemopreventive retinoid 4-HPR. Int J Cancer. 2006 Oct 1;119(7):1599-606.
• [31] MIP-1beta, a novel biomarker for in vitro sensitization test using human monocytic cell line. Toxicol In Vitro. 2006 Aug;20(5):736-42.
• [32] 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.
• [33] 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.
• [34] Expression and DNA methylation changes in human breast epithelial cells after bisphenol A exposure. Int J Oncol. 2012 Jul;41(1):369-77.
• [35] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [36] 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.
• [37] Comparative DNA microarray analysis of human monocyte derived dendritic cells and MUTZ-3 cells exposed to the moderate skin sensitizer cinnamaldehyde. Toxicol Appl Pharmacol. 2009 Sep 15;239(3):273-83.
• [38] Analysis of lead toxicity in human cells. BMC Genomics. 2012 Jul 27;13:344.
• [39] Immediate up-regulation of the calcium-binding protein S100P and its involvement in the cytokinin-induced differentiation of human myeloid leukemia cells. Biochim Biophys Acta. 2005 Sep 10;1745(2):156-65.
• [40] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.