Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT7I3DN0)

• DOT Name: Adrenodoxin, mitochondrial (FDX1)
• Synonyms: Adrenal ferredoxin; Ferredoxin-1; Hepatoredoxin
• Gene Name: FDX1
• Related Disease:
  Choriocarcinoma
  Hepatitis B virus infection
  Hepatocellular carcinoma
  IgA nephropathy
  Liver cirrhosis
  Neoplasm
  Non-small-cell lung cancer
  Pancreatitis
  Vibrio cholerae infection
  Vitamin D-dependent rickets, type 1
• UniProt ID: ADX_HUMAN
• PDB ID: 3N9Y; 3N9Z; 3NA0; 3NA1; 3P1M; 7M8I
• Pfam ID: PF00111
• Sequence:
  MAAAGGARLLRAASAVLGGPAGRWLHHAGSRAGSSGLLRNRGPGGSAEASRSLSVSARAR
  SSSEDKITVHFINRDGETLTTKGKVGDSLLDVVVENNLDIDGFGACEGTLACSTCHLIFE
  DHIYEKLDAITDEENDMLDLAYGLTDRSRLGCQICLTKSMDNMTVRVPETVADARQSIDV
  GKTS
• Function: Essential for the synthesis of various steroid hormones. Participates in the reduction of mitochondrial cytochrome P450 for steroidogenesis. Transfers electrons from adrenodoxin reductase to CYP11A1, a cytochrome P450 that catalyzes cholesterol side-chain cleavage. Does not form a ternary complex with adrenodoxin reductase and CYP11A1 but shuttles between the two enzymes to transfer electrons.
• Tissue Specificity: Highest levels in the adrenal gland (at protein level). Also detected in kidney and testis (at protein level).
• Reactome Pathway:
  Pregnenolone biosynthesis (R-HSA-196108)
  Endogenous sterols (R-HSA-211976)
  Electron transport from NADPH to Ferredoxin (R-HSA-2395516)
  Defective CYP11A1 causes AICSR (R-HSA-5579026)
  Mitochondrial iron-sulfur cluster biogenesis (R-HSA-1362409)

Molecular Interaction Atlas (MIA) of This DOT

10 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Choriocarcinoma	DISDBVNL	Strong	Biomarker	[1]
Hepatitis B virus infection	DISLQ2XY	Strong	Biomarker	[2]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[2]
IgA nephropathy	DISZ8MTK	Strong	Genetic Variation	[3]
Liver cirrhosis	DIS4G1GX	Strong	Biomarker	[2]
Neoplasm	DISZKGEW	Strong	Altered Expression	[4]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Genetic Variation	[5]
Pancreatitis	DIS0IJEF	Strong	Biomarker	[6]
Vibrio cholerae infection	DISW7E3U	Strong	Altered Expression	[1]
Vitamin D-dependent rickets, type 1	DISBF2X7	Strong	Genetic Variation	[7]

8 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 Adrenodoxin, mitochondrial (FDX1).	[8]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Adrenodoxin, mitochondrial (FDX1).	[9]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Adrenodoxin, mitochondrial (FDX1).	[10]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Adrenodoxin, mitochondrial (FDX1).	[11]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Adrenodoxin, mitochondrial (FDX1).	[12]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol increases the expression of Adrenodoxin, mitochondrial (FDX1).	[13]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Adrenodoxin, mitochondrial (FDX1).	[15]
Milchsaure	DM462BT	Investigative	Milchsaure affects the expression of Adrenodoxin, mitochondrial (FDX1).	[16]

1 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 Adrenodoxin, mitochondrial (FDX1).	[14]

References

• [1] Regulation of the cholesterol side-chain cleavage cytochrome P-450 and adrenodoxin mRNAs in cultured choriocarcinoma cells.Mol Cell Endocrinol. 1992 Apr;84(3):195-202. doi: 10.1016/0303-7207(92)90030-a.
• [2] Genome-wide association study of chronic hepatitis B virus infection reveals a novel candidate risk allele on 11q22.3.J Med Genet. 2013 Nov;50(11):725-32. doi: 10.1136/jmedgenet-2013-101724. Epub 2013 Sep 24.
• [3] Association between CCDC132, FDX1 and TNFSF13 gene polymorphisms and the risk of IgA nephropathy.Nephrology (Carlton). 2015 Dec;20(12):908-15. doi: 10.1111/nep.12611.
• [4] Adrenals Contribute to Growth of Castration-Resistant VCaP Prostate Cancer Xenografts.Am J Pathol. 2018 Dec;188(12):2890-2901. doi: 10.1016/j.ajpath.2018.07.029. Epub 2018 Sep 28.
• [5] Snapback primer mediated clamping PCR for detection of EGFR and KRAS mutations in NSCLC patients by high resolution melting analysis.Biomed Res Int. 2014;2014:407537. doi: 10.1155/2014/407537. Epub 2014 May 4.
• [6] Pancreatic gene expression during the initiation of acute pancreatitis: identification of EGR-1 as a key regulator.Physiol Genomics. 2003 Jun 24;14(1):59-72. doi: 10.1152/physiolgenomics.00174.2002.
• [7] Vitamin D-Dependent Rickets Type 1 Caused by Mutations in CYP27B1 Affecting Protein Interactions With Adrenodoxin.J Clin Endocrinol Metab. 2016 Sep;101(9):3409-18. doi: 10.1210/jc.2016-2124. Epub 2016 Jul 11.
• [8] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [9] 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.
• [10] 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.
• [11] Human 3D multicellular microtissues: an upgraded model for the in vitro mechanistic investigation of inflammation-associated drug toxicity. Toxicol Lett. 2019 Sep 15;312:34-44.
• [12] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [13] Identification of biomarkers and outcomes of endocrine disruption in human ovarian cortex using In Vitro Models. Toxicology. 2023 Feb;485:153425. doi: 10.1016/j.tox.2023.153425. Epub 2023 Jan 5.
• [14] 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.
• [15] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [16] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.