Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTJ27FOX)

• DOT Name: Cholesterol 24-hydroxylase (CYP46A1)
• Synonyms: CH24H; EC 1.14.14.25; Cholesterol 24-monooxygenase; Cholesterol 24S-hydroxylase; Cytochrome P450 46A1
• Gene Name: CYP46A1
• UniProt ID: CP46A_HUMAN
• PDB ID: 2Q9F; 2Q9G; 3MDM; 3MDR; 3MDT; 3MDV; 4ENH; 4FIA; 4J14; 7LRL; 7LS3; 7LS4; 7N3L; 7N3M; 7N6F
• EC Number: 1.14.14.25
• Pfam ID: PF00067
• Sequence:
  MSPGLLLLGSAVLLAFGLCCTFVHRARSRYEHIPGPPRPSFLLGHLPCFWKKDEVGGRVL
  QDVFLDWAKKYGPVVRVNVFHKTSVIVTSPESVKKFLMSTKYNKDSKMYRALQTVFGERL
  FGQGLVSECNYERWHKQRRVIDLAFSRSSLVSLMETFNEKAEQLVEILEAKADGQTPVSM
  QDMLTYTAMDILAKAAFGMETSMLLGAQKPLSQAVKLMLEGITASRNTLAKFLPGKRKQL
  REVRESIRFLRQVGRDWVQRRREALKRGEEVPADILTQILKAEEGAQDDEGLLDNFVTFF
  IAGHETSANHLAFTVMELSRQPEIVARLQAEVDEVIGSKRYLDFEDLGRLQYLSQVLKES
  LRLYPPAWGTFRLLEEETLIDGVRVPGNTPLLFSTYVMGRMDTYFEDPLTFNPDRFGPGA
  PKPRFTYFPFSLGHRSCIGQQFAQMEVKVVMAKLLQRLEFRLVPGQRFGLQEQATLKPLD
  PVLCTLRPRGWQPAPPPPPC
• Function: P450 monooxygenase that plays a major role in cholesterol homeostasis in the brain. Primarily catalyzes the hydroxylation (with S stereochemistry) at C-24 of cholesterol side chain, triggering cholesterol diffusion out of neurons and its further degradation. By promoting constant cholesterol elimination in neurons, may activate the mevalonate pathway and coordinate the synthesis of new cholesterol and nonsterol isoprenoids involved in synaptic activity and learning. Further hydroxylates cholesterol derivatives and hormone steroids on both the ring and side chain of these molecules, converting them into active oxysterols involved in lipid signaling and biosynthesis. Acts as an epoxidase converting cholesta-5,24-dien-3beta-ol/desmosterol into (24S),25-epoxycholesterol, an abundant lipid ligand of nuclear NR1H2 and NR1H3 receptors shown to promote neurogenesis in developing brain. May also catalyze the oxidative metabolism of xenobiotics, such as clotrimazole.
• Tissue Specificity: Expressed in brain. The mRNA was broadly distributed with higher levels in gray matter zones and lower levels in regions rich in white matter. Not detected in fetal sample but its expression increases linearly with age.
• 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)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Biotransformations of 8 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Testosterone	DM7HUNW	Approved	Cholesterol 24-hydroxylase (CYP46A1) increases the hydroxylation of Testosterone.	[7]
Progesterone	DMUY35B	Approved	Cholesterol 24-hydroxylase (CYP46A1) increases the hydroxylation of Progesterone.	[7]
Diclofenac	DMPIHLS	Approved	Cholesterol 24-hydroxylase (CYP46A1) increases the hydroxylation of Diclofenac.	[7]
Dextromethorphan	DMUDJZM	Approved	Cholesterol 24-hydroxylase (CYP46A1) decreases the methylation of Dextromethorphan.	[7]
ANW-32821	DMMJOZD	Phase 2	Cholesterol 24-hydroxylase (CYP46A1) increases the hydroxylation of ANW-32821.	[7]
Phenacetin	DMRQAM0	Withdrawn from market	Cholesterol 24-hydroxylase (CYP46A1) decreases the ethylation of Phenacetin.	[7]
24(S)-hydroxycholesterol	DMGMWA6	Investigative	Cholesterol 24-hydroxylase (CYP46A1) increases the chemical synthesis of 24(S)-hydroxycholesterol.	[7]
7alpha-hydroxycholesterol	DMH6LD0	Investigative	Cholesterol 24-hydroxylase (CYP46A1) increases the hydroxylation of 7alpha-hydroxycholesterol.	[7]

4 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 Cholesterol 24-hydroxylase (CYP46A1).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Cholesterol 24-hydroxylase (CYP46A1).	[2]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Cholesterol 24-hydroxylase (CYP46A1).	[4]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Cholesterol 24-hydroxylase (CYP46A1).	[6]

2 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 Cholesterol 24-hydroxylase (CYP46A1).	[3]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Cholesterol 24-hydroxylase (CYP46A1).	[5]

References

• [1] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [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] 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.
• [4] The molecular basis of genistein-induced mitotic arrest and exit of self-renewal in embryonal carcinoma and primary cancer cell lines. BMC Med Genomics. 2008 Oct 10;1:49.
• [5] Effect of aflatoxin B(1), benzo[a]pyrene, and methapyrilene on transcriptomic and epigenetic alterations in human liver HepaRG cells. Food Chem Toxicol. 2018 Nov;121:214-223. doi: 10.1016/j.fct.2018.08.034. Epub 2018 Aug 26.
• [6] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [7] Broad substrate specificity of human cytochrome P450 46A1 which initiates cholesterol degradation in the brain. Biochemistry. 2003 Dec 9;42(48):14284-92.