Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT2FZP6H)

• DOT Name: Aldehyde oxidase (AOX1)
• Synonyms: EC 1.2.3.1; Aldehyde oxidase 1; Azaheterocycle hydroxylase; EC 1.17.3.-
• Gene Name: AOX1
• UniProt ID: AOXA_HUMAN
• PDB ID: 4UHW; 4UHX; 5EPG; 6Q6Q; 7OPN; 7ORC; 8EMT
• EC Number: 1.17.3.-; 1.2.3.1
• Pfam ID: PF01315 ; PF03450 ; PF00941 ; PF00111 ; PF01799 ; PF02738 ; PF20256
• Sequence:
  MDRASELLFYVNGRKVIEKNVDPETMLLPYLRKKLRLTGTKYGCGGGGCGACTVMISRYN
  PITKRIRHHPANACLIPICSLYGAAVTTVEGIGSTHTRIHPVQERIAKCHGTQCGFCTPG
  MVMSIYTLLRNHPEPTLDQLTDALGGNLCRCTGYRPIIDACKTFCKTSGCCQSKENGVCC
  LDQGINGLPEFEEGSKTSPKLFAEEEFLPLDPTQELIFPPELMIMAEKQSQRTRVFGSER
  MMWFSPVTLKELLEFKFKYPQAPVIMGNTSVGPEVKFKGVFHPVIISPDRIEELSVVNHA
  YNGLTLGAGLSLAQVKDILADVVQKLPEEKTQMYHALLKHLGTLAGSQIRNMASLGGHII
  SRHPDSDLNPILAVGNCTLNLLSKEGKRQIPLNEQFLSKCPNADLKPQEILVSVNIPYSR
  KWEFVSAFRQAQRQENALAIVNSGMRVFFGEGDGIIRELCISYGGVGPATICAKNSCQKL
  IGRHWNEQMLDIACRLILNEVSLLGSAPGGKVEFKRTLIISFLFKFYLEVSQILKKMDPV
  HYPSLADKYESALEDLHSKHHCSTLKYQNIGPKQHPEDPIGHPIMHLSGVKHATGEAIYC
  DDMPLVDQELFLTFVTSSRAHAKIVSIDLSEALSMPGVVDIMTAEHLSDVNSFCFFTEAE
  KFLATDKVFCVGQLVCAVLADSEVQAKRAAKRVKIVYQDLEPLILTIEESIQHNSSFKPE
  RKLEYGNVDEAFKVVDQILEGEIHMGGQEHFYMETQSMLVVPKGEDQEMDVYVSTQFPKY
  IQDIVASTLKLPANKVMCHVRRVGGAFGGKVLKTGIIAAVTAFAANKHGRAVRCVLERGE
  DMLITGGRHPYLGKYKAGFMNDGRILALDMEHYSNAGASLDESLFVIEMGLLKMDNAYKF
  PNLRCRGWACRTNLPSNTAFRGFGFPQAALITESCITEVAAKCGLSPEKVRIINMYKEID
  QTPYKQEINAKNLIQCWRECMAMSSYSLRKVAVEKFNAENYWKKKGLAMVPLKFPVGLGS
  RAAGQAAALVHIYLDGSVLVTHGGIEMGQGVHTKMIQVVSRELRMPMSNVHLRGTSTETV
  PNANISGGSVVADLNGLAVKDACQTLLKRLEPIISKNPKGTWKDWAQTAFDESINLSAVG
  YFRGYESDMNWEKGEGQPFEYFVYGAACSEVEIDCLTGDHKNIRTDIVMDVGCSINPAID
  IGQIEGAFIQGMGLYTIEELNYSPQGILHTRGPDQYKIPAICDMPTELHIALLPPSQNSN
  TLYSSKGLGESGVFLGCSVFFAIHDAVSAARQERGLHGPLTLNSPLTPEKIRMACEDKFT
  KMIPRDEPGSYVPWNVPI
• Function: Oxidase with broad substrate specificity, oxidizing aromatic azaheterocycles, such as N1-methylnicotinamide, N-methylphthalazinium and phthalazine, as well as aldehydes, such as benzaldehyde, retinal, pyridoxal, and vanillin. Plays a key role in the metabolism of xenobiotics and drugs containing aromatic azaheterocyclic substituents. Participates in the bioactivation of prodrugs such as famciclovir, catalyzing the oxidation step from 6-deoxypenciclovir to penciclovir, which is a potent antiviral agent. Is probably involved in the regulation of reactive oxygen species homeostasis. May be a prominent source of superoxide generation via the one-electron reduction of molecular oxygen. May also catalyze nitric oxide (NO) production via the reduction of nitrite to NO with NADH or aldehyde as electron donor. May play a role in adipogenesis.
• Tissue Specificity: Abundant in liver, expressed in adipose tissue and at lower levels in lung, skeletal muscle, pancreas. In contrast to mice, no significant gender difference in AOX1 expression level (at protein level).
• KEGG Pathway:
  Valine, leucine and isoleucine degradation (hsa00280)
  Tyrosine metabolism (hsa00350)
  Tryptophan metabolism (hsa00380)
  Vitamin B6 metabolism (hsa00750)
  Nicoti.te and nicoti.mide metabolism (hsa00760)
  Retinol metabolism (hsa00830)
  Drug metabolism - cytochrome P450 (hsa00982)
  Metabolic pathways (hsa01100)
  JAK-STAT sig.ling pathway (hsa04630)
• Reactome Pathway: Vitamin B6 activation to pyridoxal phosphate (R-HSA-964975)
• BioCyc Pathway: MetaCyc:ENSG00000138356-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Drug Response of 5 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Aldehyde oxidase (AOX1) affects the response to substance of Doxorubicin.	[28]
Paclitaxel	DMLB81S	Approved	Aldehyde oxidase (AOX1) affects the response to substance of Paclitaxel.	[28]
Mitomycin	DMH0ZJE	Approved	Aldehyde oxidase (AOX1) affects the response to substance of Mitomycin.	[28]
Topotecan	DMP6G8T	Approved	Aldehyde oxidase (AOX1) affects the response to substance of Topotecan.	[28]
Vinblastine	DM5TVS3	Approved	Aldehyde oxidase (AOX1) affects the response to substance of Vinblastine.	[28]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
XR-5000	DMOKUA5	Phase 2	Aldehyde oxidase (AOX1) affects the metabolism of XR-5000.	[29]
XK-469	DMVYO41	Phase 1	Aldehyde oxidase (AOX1) affects the metabolism of XK-469.	[29]
PF-4217903	DMU2A6D	Phase 1	Aldehyde oxidase (AOX1) affects the metabolism of PF-4217903.	[29]
RS-8359	DMERM0K	Discontinued in Phase 2	Aldehyde oxidase (AOX1) affects the metabolism of RS-8359.	[29]
6-Benzyloxy-9H-purin-2-ylamine	DMFI7A8	Investigative	Aldehyde oxidase (AOX1) affects the metabolism of 6-Benzyloxy-9H-purin-2-ylamine.	[29]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Aldehyde oxidase (AOX1).	[1]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Aldehyde oxidase (AOX1).	[22]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Aldehyde oxidase (AOX1).	[24]

26 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Aldehyde oxidase (AOX1).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Aldehyde oxidase (AOX1).	[3]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Aldehyde oxidase (AOX1).	[4]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Aldehyde oxidase (AOX1).	[5]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Aldehyde oxidase (AOX1).	[6]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Aldehyde oxidase (AOX1).	[7]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Aldehyde oxidase (AOX1).	[8]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Aldehyde oxidase (AOX1).	[9]
Menadione	DMSJDTY	Approved	Menadione decreases the activity of Aldehyde oxidase (AOX1).	[10]
Panobinostat	DM58WKG	Approved	Panobinostat decreases the expression of Aldehyde oxidase (AOX1).	[11]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Aldehyde oxidase (AOX1).	[12]
Azathioprine	DMMZSXQ	Approved	Azathioprine increases the expression of Aldehyde oxidase (AOX1).	[13]
Dasatinib	DMJV2EK	Approved	Dasatinib decreases the expression of Aldehyde oxidase (AOX1).	[14]
Permethrin	DMZ0Q1G	Approved	Permethrin increases the expression of Aldehyde oxidase (AOX1).	[15]
Prednisolone	DMQ8FR2	Approved	Prednisolone increases the expression of Aldehyde oxidase (AOX1).	[13]
Rofecoxib	DM3P5DA	Approved	Rofecoxib decreases the expression of Aldehyde oxidase (AOX1).	[16]
Nefazodone	DM4ZS8M	Approved	Nefazodone decreases the expression of Aldehyde oxidase (AOX1).	[17]
Methylprednisolone	DM4BDON	Approved	Methylprednisolone increases the expression of Aldehyde oxidase (AOX1).	[13]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Aldehyde oxidase (AOX1).	[18]
Isoflavone	DM7U58J	Phase 4	Isoflavone affects the expression of Aldehyde oxidase (AOX1).	[19]
Belinostat	DM6OC53	Phase 2	Belinostat decreases the expression of Aldehyde oxidase (AOX1).	[20]
CERC-801	DM3SZ7P	Phase 2	CERC-801 increases the expression of Aldehyde oxidase (AOX1).	[21]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Aldehyde oxidase (AOX1).	[23]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Aldehyde oxidase (AOX1).	[25]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Aldehyde oxidase (AOX1).	[26]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of Aldehyde oxidase (AOX1).	[27]

References

• [1] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [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] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [4] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [5] Long-term estrogen exposure promotes carcinogen bioactivation, induces persistent changes in gene expression, and enhances the tumorigenicity of MCF-7 human breast cancer cells. Toxicol Appl Pharmacol. 2009 Nov 1;240(3):355-66.
• [6] 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.
• [7] 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.
• [8] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [9] Endometrial receptivity is affected in women with high circulating progesterone levels at the end of the follicular phase: a functional genomics analysis. Hum Reprod. 2011 Jul;26(7):1813-25.
• [10] Cross-species comparison of the metabolism and excretion of zoniporide: contribution of aldehyde oxidase to interspecies differences. Drug Metab Dispos. 2010 Apr;38(4):641-54. doi: 10.1124/dmd.109.030783. Epub 2009 Dec 29.
• [11] 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.
• [12] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [13] Antirheumatic drug response signatures in human chondrocytes: potential molecular targets to stimulate cartilage regeneration. Arthritis Res Ther. 2009;11(1):R15.
• [14] Dasatinib reverses cancer-associated fibroblasts (CAFs) from primary lung carcinomas to a phenotype comparable to that of normal fibroblasts. Mol Cancer. 2010 Jun 27;9:168.
• [15] Exposure to Insecticides Modifies Gene Expression and DNA Methylation in Hematopoietic Tissues In Vitro. Int J Mol Sci. 2023 Mar 26;24(7):6259. doi: 10.3390/ijms24076259.
• [16] Rofecoxib modulates multiple gene expression pathways in a clinical model of acute inflammatory pain. Pain. 2007 Mar;128(1-2):136-47.
• [17] Robustness testing and optimization of an adverse outcome pathway on cholestatic liver injury. Arch Toxicol. 2020 Apr;94(4):1151-1172. doi: 10.1007/s00204-020-02691-9. Epub 2020 Mar 10.
• [18] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [19] 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.
• [20] 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.
• [21] Hydrogen sulfide protects SH-SY5Y neuronal cells against d-galactose induced cell injury by suppression of advanced glycation end products formation and oxidative stress. Neurochem Int. 2013 Apr;62(5):603-9.
• [22] 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.
• [23] 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.
• [24] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [25] 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.
• [26] 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.
• [27] Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.
• [28] 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.
• [29] In vitro-in vivo correlation for intrinsic clearance for drugs metabolized by human aldehyde oxidase. Drug Metab Dispos. 2010 Aug;38(8):1322-7. doi: 10.1124/dmd.110.033555. Epub 2010 May 5.