Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTT40HOD)

• DOT Name: Xanthine dehydrogenase/oxidase
• Gene Name: XDH
• Related Disease: Xanthinuria type I
• UniProt ID: XDH_HUMAN
• PDB ID: 2CKJ; 2E1Q
• EC Number: 1.17.1.4; 1.17.3.2
• Pfam ID: PF01315 ; PF03450 ; PF00941 ; PF00111 ; PF01799 ; PF02738 ; PF20256
• Sequence:
  MTADKLVFFVNGRKVVEKNADPETTLLAYLRRKLGLSGTKLGCGEGGCGACTVMLSKYDR
  LQNKIVHFSANACLAPICSLHHVAVTTVEGIGSTKTRLHPVQERIAKSHGSQCGFCTPGI
  VMSMYTLLRNQPEPTMEEIENAFQGNLCRCTGYRPILQGFRTFARDGGCCGGDGNNPNCC
  MNQKKDHSVSLSPSLFKPEEFTPLDPTQEPIFPPELLRLKDTPRKQLRFEGERVTWIQAS
  TLKELLDLKAQHPDAKLVVGNTEIGIEMKFKNMLFPMIVCPAWIPELNSVEHGPDGISFG
  AACPLSIVEKTLVDAVAKLPAQKTEVFRGVLEQLRWFAGKQVKSVASVGGNIITASPISD
  LNPVFMASGAKLTLVSRGTRRTVQMDHTFFPGYRKTLLSPEEILLSIEIPYSREGEYFSA
  FKQASRREDDIAKVTSGMRVLFKPGTTEVQELALCYGGMANRTISALKTTQRQLSKLWKE
  ELLQDVCAGLAEELHLPPDAPGGMVDFRCTLTLSFFFKFYLTVLQKLGQENLEDKCGKLD
  PTFASATLLFQKDPPADVQLFQEVPKGQSEEDMVGRPLPHLAADMQASGEAVYCDDIPRY
  ENELSLRLVTSTRAHAKIKSIDTSEAKKVPGFVCFISADDVPGSNITGICNDETVFAKDK
  VTCVGHIIGAVVADTPEHTQRAAQGVKITYEELPAIITIEDAIKNNSFYGPELKIEKGDL
  KKGFSEADNVVSGEIYIGGQEHFYLETHCTIAVPKGEAGEMELFVSTQNTMKTQSFVAKM
  LGVPANRIVVRVKRMGGGFGGKETRSTVVSTAVALAAYKTGRPVRCMLDRDEDMLITGGR
  HPFLARYKVGFMKTGTVVALEVDHFSNVGNTQDLSQSIMERALFHMDNCYKIPNIRGTGR
  LCKTNLPSNTAFRGFGGPQGMLIAECWMSEVAVTCGMPAEEVRRKNLYKEGDLTHFNQKL
  EGFTLPRCWEECLASSQYHARKSEVDKFNKENCWKKRGLCIIPTKFGISFTVPFLNQAGA
  LLHVYTDGSVLLTHGGTEMGQGLHTKMVQVASRALKIPTSKIYISETSTNTVPNTSPTAA
  SVSADLNGQAVYAACQTILKRLEPYKKKNPSGSWEDWVTAAYMDTVSLSATGFYRTPNLG
  YSFETNSGNPFHYFSYGVACSEVEIDCLTGDHKNLRTDIVMDVGSSLNPAIDIGQVEGAF
  VQGLGLFTLEELHYSPEGSLHTRGPSTYKIPAFGSIPIEFRVSLLRDCPNKKAIYASKAV
  GEPPLFLAASIFFAIKDAIRAARAQHTGNNVKELFRLDSPATPEKIRNACVDKFTTLCVT
  GVPENCKPWSVRV
• Function: Key enzyme in purine degradation. Catalyzes the oxidation of hypoxanthine to xanthine. Catalyzes the oxidation of xanthine to uric acid. Contributes to the generation of reactive oxygen species. Has also low oxidase activity towards aldehydes (in vitro).
• Tissue Specificity: Detected in milk (at protein level).
• KEGG Pathway:
  Purine metabolism (hsa00230)
  Caffeine metabolism (hsa00232)
  Drug metabolism - other enzymes (hsa00983)
  Metabolic pathways (hsa01100)
  Nucleotide metabolism (hsa01232)
  Peroxisome (hsa04146)
• Reactome Pathway:
  Butyrophilin (BTN) family interactions (R-HSA-8851680)
  Azathioprine ADME (R-HSA-9748787)
  Purine catabolism (R-HSA-74259)
• BioCyc Pathway: MetaCyc:HS08270-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Xanthinuria type I	DISIRVYD	Strong	Autosomal recessive	[1]

This DOT Affected the Regulation of Drug Effects of 5 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Dextromethorphan	DMUDJZM	Approved	Xanthine dehydrogenase/oxidase affects the metabolism of Dextromethorphan.	[25]
Chlorzoxazone	DMCYVDT	Approved	Xanthine dehydrogenase/oxidase affects the metabolism of Chlorzoxazone.	[26]
PMID28870136-Compound-52	DMFDERP	Patented	Xanthine dehydrogenase/oxidase affects the metabolism of PMID28870136-Compound-52.	[27]
1-METHYLXANTHINE	DM2WQ1E	Investigative	Xanthine dehydrogenase/oxidase increases the metabolism of 1-METHYLXANTHINE.	[7]
Hypoxanthine	DMLSABI	Investigative	Xanthine dehydrogenase/oxidase affects the metabolism of Hypoxanthine.	[29]

This DOT Affected the Biotransformations of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Uric acid	DMA1MKT	Investigative	Xanthine dehydrogenase/oxidase increases the chemical synthesis of Uric acid.	[28]

23 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 Xanthine dehydrogenase/oxidase .	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Xanthine dehydrogenase/oxidase .	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Xanthine dehydrogenase/oxidase .	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Xanthine dehydrogenase/oxidase .	[5]
Quercetin	DM3NC4M	Approved	Quercetin increases the activity of Xanthine dehydrogenase/oxidase .	[7]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the activity of Xanthine dehydrogenase/oxidase .	[8]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Xanthine dehydrogenase/oxidase .	[9]
Ethanol	DMDRQZU	Approved	Ethanol increases the expression of Xanthine dehydrogenase/oxidase .	[10]
Indomethacin	DMSC4A7	Approved	Indomethacin increases the activity of Xanthine dehydrogenase/oxidase .	[11]
Mitomycin	DMH0ZJE	Approved	Mitomycin decreases the activity of Xanthine dehydrogenase/oxidase .	[12]
Permethrin	DMZ0Q1G	Approved	Permethrin increases the expression of Xanthine dehydrogenase/oxidase .	[13]
Obeticholic acid	DM3Q1SM	Approved	Obeticholic acid increases the expression of Xanthine dehydrogenase/oxidase .	[14]
Bosentan	DMIOGBU	Approved	Bosentan decreases the expression of Xanthine dehydrogenase/oxidase .	[15]
Allopurinol	DMLPAOB	Approved	Allopurinol decreases the activity of Xanthine dehydrogenase/oxidase .	[16]
Febuxostat	DMDEXQ0	Approved	Febuxostat decreases the activity of Xanthine dehydrogenase/oxidase .	[17]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Xanthine dehydrogenase/oxidase .	[18]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Xanthine dehydrogenase/oxidase .	[19]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Xanthine dehydrogenase/oxidase .	[20]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Xanthine dehydrogenase/oxidase .	[21]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Xanthine dehydrogenase/oxidase .	[22]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of Xanthine dehydrogenase/oxidase .	[10]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of Xanthine dehydrogenase/oxidase .	[23]
methylglyoxal	DMRC3OZ	Investigative	methylglyoxal increases the expression of Xanthine dehydrogenase/oxidase .	[24]

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 Xanthine dehydrogenase/oxidase .	[6]

References

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• [7] Simultaneous action of the flavonoid quercetin on cytochrome P450 (CYP) 1A2, CYP2A6, N-acetyltransferase and xanthine oxidase activity in healthy volunteers. Clin Exp Pharmacol Physiol. 2009 Aug;36(8):828-33.
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• [19] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [20] 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.
• [21] Cystathionine metabolic enzymes play a role in the inflammation resolution of human keratinocytes in response to sub-cytotoxic formaldehyde exposure. Toxicol Appl Pharmacol. 2016 Nov 1;310:185-194.
• [22] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [23] Persistence of epigenomic effects after recovery from repeated treatment with two nephrocarcinogens. Front Genet. 2018 Dec 3;9:558.
• [24] Liraglutide reduces oxidative stress and improves energy metabolism in methylglyoxal-induced SH-SY5Y cells. Neurotoxicology. 2022 Sep;92:166-179. doi: 10.1016/j.neuro.2022.08.007. Epub 2022 Aug 17.
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• [26] Effects of cigarette smoking and carbon monoxide on chlorzoxazone and caffeine metabolism. Clin Pharmacol Ther. 2003 Nov;74(5):468-74. doi: 10.1016/j.clpt.2003.07.001.
• [27] Combined phenotypic assessment of cytochrome p450 1A2, 2C9, 2C19, 2D6, and 3A, N-acetyltransferase-2, and xanthine oxidase activities with the "Cooperstown 5+1 cocktail". Clin Pharmacol Ther. 2003 Nov;74(5):437-47.
• [28] Ketohexokinase-dependent metabolism of fructose induces proinflammatory mediators in proximal tubular cells. J Am Soc Nephrol. 2009 Mar;20(3):545-53. doi: 10.1681/ASN.2008060576. Epub 2009 Jan 21.
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