Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTPDCK1F)

• DOT Name: NADPH:adrenodoxin oxidoreductase, mitochondrial (FDXR)
• Synonyms: AR; Adrenodoxin reductase; EC 1.18.1.6; Ferredoxin--NADP(+) reductase; Ferredoxin reductase
• Gene Name: FDXR
• Related Disease:
  Auditory neuropathy-optic atrophy syndrome
  Optic atrophy-ataxia-peripheral neuropathy-global developmental delay syndrome
• UniProt ID: ADRO_HUMAN
• EC Number: 1.18.1.6
• Pfam ID: PF07992
• Sequence:
  MASRCWRWWGWSAWPRTRLPPAGSTPSFCHHFSTQEKTPQICVVGSGPAGFYTAQHLLKH
  PQAHVDIYEKQPVPFGLVRFGVAPDHPEVKNVINTFTQTAHSGRCAFWGNVEVGRDVTVP
  ELREAYHAVVLSYGAEDHRALEIPGEELPGVCSARAFVGWYNGLPENQELEPDLSCDTAV
  ILGQGNVALDVARILLTPPEHLERTDITKAALGVLRQSRVKTVWLVGRRGPLQVAFTIKE
  LREMIQLPGARPILDPVDFLGLQDKIKEVPRPRKRLTELLLRTATEKPGPAEAARQASAS
  RAWGLRFFRSPQQVLPSPDGRRAAGVRLAVTRLEGVDEATRAVPTGDMEDLPCGLVLSSI
  GYKSRPVDPSVPFDSKLGVIPNVEGRVMDVPGLYCSGWVKRGPTGVIATTMTDSFLTGQM
  LLQDLKAGLLPSGPRPGYAAIQALLSSRGVRPVSFSDWEKLDAEEVARGQGTGKPREKLV
  DPQEMLRLLGH
• Function: Serves as the first electron transfer protein in all the mitochondrial P450 systems including cholesterol side chain cleavage in all steroidogenic tissues, steroid 11-beta hydroxylation in the adrenal cortex, 25-OH-vitamin D3-24 hydroxylation in the kidney, and sterol C-27 hydroxylation in the liver.
• Reactome Pathway:
  Endogenous sterols (R-HSA-211976)
  Electron transport from NADPH to Ferredoxin (R-HSA-2395516)
  Defective CYP11A1 causes AICSR (R-HSA-5579026)
  Pregnenolone biosynthesis (R-HSA-196108)
• BioCyc Pathway: MetaCyc:HS08587-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Auditory neuropathy-optic atrophy syndrome	DISM0JK2	Strong	Autosomal recessive	[1]
Optic atrophy-ataxia-peripheral neuropathy-global developmental delay syndrome	DISIGVK9	Supportive	Autosomal recessive	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of NADPH:adrenodoxin oxidoreductase, mitochondrial (FDXR).	[3]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of NADPH:adrenodoxin oxidoreductase, mitochondrial (FDXR).	[9]

24 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 NADPH:adrenodoxin oxidoreductase, mitochondrial (FDXR).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of NADPH:adrenodoxin oxidoreductase, mitochondrial (FDXR).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of NADPH:adrenodoxin oxidoreductase, mitochondrial (FDXR).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of NADPH:adrenodoxin oxidoreductase, mitochondrial (FDXR).	[7]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of NADPH:adrenodoxin oxidoreductase, mitochondrial (FDXR).	[8]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of NADPH:adrenodoxin oxidoreductase, mitochondrial (FDXR).	[10]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the expression of NADPH:adrenodoxin oxidoreductase, mitochondrial (FDXR).	[11]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of NADPH:adrenodoxin oxidoreductase, mitochondrial (FDXR).	[12]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of NADPH:adrenodoxin oxidoreductase, mitochondrial (FDXR).	[13]
Menadione	DMSJDTY	Approved	Menadione increases the expression of NADPH:adrenodoxin oxidoreductase, mitochondrial (FDXR).	[11]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil increases the expression of NADPH:adrenodoxin oxidoreductase, mitochondrial (FDXR).	[6]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of NADPH:adrenodoxin oxidoreductase, mitochondrial (FDXR).	[14]
Etoposide	DMNH3PG	Approved	Etoposide increases the expression of NADPH:adrenodoxin oxidoreductase, mitochondrial (FDXR).	[15]
Daunorubicin	DMQUSBT	Approved	Daunorubicin increases the expression of NADPH:adrenodoxin oxidoreductase, mitochondrial (FDXR).	[15]
Colchicine	DM2POTE	Approved	Colchicine decreases the expression of NADPH:adrenodoxin oxidoreductase, mitochondrial (FDXR).	[16]
Adenine	DMZLHKJ	Approved	Adenine decreases the expression of NADPH:adrenodoxin oxidoreductase, mitochondrial (FDXR).	[16]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of NADPH:adrenodoxin oxidoreductase, mitochondrial (FDXR).	[17]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of NADPH:adrenodoxin oxidoreductase, mitochondrial (FDXR).	[18]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of NADPH:adrenodoxin oxidoreductase, mitochondrial (FDXR).	[19]
Camptothecin	DM6CHNJ	Phase 3	Camptothecin increases the expression of NADPH:adrenodoxin oxidoreductase, mitochondrial (FDXR).	[15]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of NADPH:adrenodoxin oxidoreductase, mitochondrial (FDXR).	[20]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of NADPH:adrenodoxin oxidoreductase, mitochondrial (FDXR).	[21]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of NADPH:adrenodoxin oxidoreductase, mitochondrial (FDXR).	[22]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of NADPH:adrenodoxin oxidoreductase, mitochondrial (FDXR).	[14]

References

• [1] FDXR Mutations Cause Sensorial Neuropathies and Expand the Spectrum of Mitochondrial Fe-S-Synthesis Diseases. Am J Hum Genet. 2017 Oct 5;101(4):630-637. doi: 10.1016/j.ajhg.2017.09.007. Epub 2017 Sep 28.
• [2] Biallelic mutations in the ferredoxin reductase gene cause novel mitochondriopathy with optic atrophy. Hum Mol Genet. 2017 Dec 15;26(24):4937-4950. doi: 10.1093/hmg/ddx377.
• [3] 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.
• [4] 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.
• [5] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [6] Cell-type-specific responses to chemotherapeutics in breast cancer. Cancer Res. 2004 Jun 15;64(12):4218-26.
• [7] The thioxotriazole copper(II) complex A0 induces endoplasmic reticulum stress and paraptotic death in human cancer cells. J Biol Chem. 2009 Sep 4;284(36):24306-19.
• [8] 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.
• [9] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [10] 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.
• [11] Gene expression after treatment with hydrogen peroxide, menadione, or t-butyl hydroperoxide in breast cancer cells. Cancer Res. 2002 Nov 1;62(21):6246-54.
• [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] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [15] Characterization of DNA reactive and non-DNA reactive anticancer drugs by gene expression profiling. Mutat Res. 2007 Jun 1;619(1-2):16-29. doi: 10.1016/j.mrfmmm.2006.12.007. Epub 2007 Feb 8.
• [16] Utilization of CDKN1A/p21 gene for class discrimination of DNA damage-induced clastogenicity. Toxicology. 2014 Jan 6;315:8-16. doi: 10.1016/j.tox.2013.10.009. Epub 2013 Nov 6.
• [17] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [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] A novel long noncoding RNA AK001796 acts as an oncogene and is involved in cell growth inhibition by resveratrol in lung cancer. Toxicol Appl Pharmacol. 2015 Jun 1;285(2):79-88.
• [20] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [21] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [22] The interference effects of bisphenol A on the synthesis of steroid hormones in human ovarian granulosa cells. Environ Toxicol. 2021 Apr;36(4):665-674. doi: 10.1002/tox.23070. Epub 2020 Dec 1.