Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTBAJT4I)

• DOT Name: 24-hydroxycholesterol 7-alpha-hydroxylase (CYP39A1)
• Synonyms: EC 1.14.14.26; Cytochrome P450 39A1; hCYP39A1; Oxysterol 7-alpha-hydroxylase
• Gene Name: CYP39A1
• UniProt ID: CP39A_HUMAN
• EC Number: 1.14.14.26
• Pfam ID: PF00067
• Sequence:
  MELISPTVIIILGCLALFLLLQRKNLRRPPCIKGWIPWIGVGFEFGKAPLEFIEKARIKY
  GPIFTVFAMGNRMTFVTEEEGINVFLKSKKVDFELAVQNIVYRTASIPKNVFLALHEKLY
  IMLKGKMGTVNLHQFTGQLTEELHEQLENLGTHGTMDLNNLVRHLLYPVTVNMLFNKSLF
  STNKKKIKEFHQYFQVYDEDFEYGSQLPECLLRNWSKSKKWFLELFEKNIPDIKACKSAK
  DNSMTLLQATLDIVETETSKENSPNYGLLLLWASLSNAVPVAFWTLAYVLSHPDIHKAIM
  EGISSVFGKAGKDKIKVSEDDLENLLLIKWCVLETIRLKAPGVITRKVVKPVEILNYIIP
  SGDLLMLSPFWLHRNPKYFPEPELFKPERWKKANLEKHSFLDCFMAFGSGKFQCPARWFA
  LLEVQMCIILILYKYDCSLLDPLPKQSYLHLVGVPQPEGQCRIEYKQRI
• Function: A cytochrome P450 monooxygenase involved in neural cholesterol clearance through bile acid synthesis. Catalyzes 7-alpha hydroxylation of (24S)-hydroxycholesterol, a neural oxysterol that is metabolized to bile acids in the liver. Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (CPR; NADPH-ferrihemoprotein reductase).
• Tissue Specificity: Liver specific.
• KEGG Pathway: Primary bile acid biosynthesis (hsa00120)
• Reactome Pathway:
  Endogenous sterols (R-HSA-211976)
  Synthesis of bile acids and bile salts via 24-hydroxycholesterol (R-HSA-193775)
• BioCyc Pathway: MetaCyc:HS07335-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

15 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 24-hydroxycholesterol 7-alpha-hydroxylase (CYP39A1).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of 24-hydroxycholesterol 7-alpha-hydroxylase (CYP39A1).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of 24-hydroxycholesterol 7-alpha-hydroxylase (CYP39A1).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of 24-hydroxycholesterol 7-alpha-hydroxylase (CYP39A1).	[4]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of 24-hydroxycholesterol 7-alpha-hydroxylase (CYP39A1).	[5]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of 24-hydroxycholesterol 7-alpha-hydroxylase (CYP39A1).	[6]
Carbamazepine	DMZOLBI	Approved	Carbamazepine increases the expression of 24-hydroxycholesterol 7-alpha-hydroxylase (CYP39A1).	[7]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of 24-hydroxycholesterol 7-alpha-hydroxylase (CYP39A1).	[9]
Obeticholic acid	DM3Q1SM	Approved	Obeticholic acid decreases the expression of 24-hydroxycholesterol 7-alpha-hydroxylase (CYP39A1).	[10]
Belinostat	DM6OC53	Phase 2	Belinostat increases the expression of 24-hydroxycholesterol 7-alpha-hydroxylase (CYP39A1).	[6]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of 24-hydroxycholesterol 7-alpha-hydroxylase (CYP39A1).	[11]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of 24-hydroxycholesterol 7-alpha-hydroxylase (CYP39A1).	[12]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of 24-hydroxycholesterol 7-alpha-hydroxylase (CYP39A1).	[13]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane increases the expression of 24-hydroxycholesterol 7-alpha-hydroxylase (CYP39A1).	[14]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A increases the expression of 24-hydroxycholesterol 7-alpha-hydroxylase (CYP39A1).	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of 24-hydroxycholesterol 7-alpha-hydroxylase (CYP39A1).	[8]

References

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• [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] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [4] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [5] Arsenic suppresses gene expression in promyelocytic leukemia cells partly through Sp1 oxidation. Blood. 2005 Jul 1;106(1):304-10.
• [6] 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.
• [7] Transcriptional profiling of genes induced in the livers of patients treated with carbamazepine. Clin Pharmacol Ther. 2006 Nov;80(5):440-456.
• [8] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [9] Computational discovery of niclosamide ethanolamine, a repurposed drug candidate that reduces growth of hepatocellular carcinoma cells initro and in mice by inhibiting cell division cycle 37 signaling. Gastroenterology. 2017 Jun;152(8):2022-2036.
• [10] Pharmacotoxicology of clinically-relevant concentrations of obeticholic acid in an organotypic human hepatocyte system. Toxicol In Vitro. 2017 Mar;39:93-103.
• [11] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [12] 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.
• [13] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [14] 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.
• [15] Persistence of epigenomic effects after recovery from repeated treatment with two nephrocarcinogens. Front Genet. 2018 Dec 3;9:558.