Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT0L1M1D)

• DOT Name: Vitamin D 25-hydroxylase (CYP2R1)
• Synonyms: EC 1.14.14.24; Cytochrome P450 2R1
• Gene Name: CYP2R1
• Related Disease:
  Vitamin D hydroxylation-deficient rickets, type 1B
  Vitamin D-dependent rickets, type 1
• UniProt ID: CP2R1_HUMAN
• PDB ID: 3C6G; 3CZH; 3DL9
• EC Number: 1.14.14.24
• Pfam ID: PF00067
• Sequence:
  MWKLWRAEEGAAALGGALFLLLFALGVRQLLKQRRPMGFPPGPPGLPFIGNIYSLAASSE
  LPHVYMRKQSQVYGEIFSLDLGGISTVVLNGYDVVKECLVHQSEIFADRPCLPLFMKMTK
  MGGLLNSRYGRGWVDHRRLAVNSFRYFGYGQKSFESKILEETKFFNDAIETYKGRPFDFK
  QLITNAVSNITNLIIFGERFTYEDTDFQHMIELFSENVELAASASVFLYNAFPWIGILPF
  GKHQQLFRNAAVVYDFLSRLIEKASVNRKPQLPQHFVDAYLDEMDQGKNDPSSTFSKENL
  IFSVGELIIAGTETTTNVLRWAILFMALYPNIQGQVQKEIDLIMGPNGKPSWDDKCKMPY
  TEAVLHEVLRFCNIVPLGIFHATSEDAVVRGYSIPKGTTVITNLYSVHFDEKYWRDPEVF
  HPERFLDSSGYFAKKEALVPFSLGRRHCLGEHLARMEMFLFFTALLQRFHLHFPHELVPD
  LKPRLGMTLQPQPYLICAERR
• Function: A cytochrome P450 monooxygenase involved in activation of vitamin D precursors. Catalyzes hydroxylation at C-25 of both forms of vitamin D, vitamin D(2) and D(3) (calciol). Can metabolize vitamin D analogs/prodrugs 1alpha-hydroxyvitamin D(2) (doxercalciferol) and 1alpha-hydroxyvitamin D(3) (alfacalcidol) forming 25-hydroxy derivatives. 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).
• KEGG Pathway:
  Steroid biosynthesis (hsa00100)
  Metabolic pathways (hsa01100)
• Reactome Pathway:
  Vitamins (R-HSA-211916)
  Defective CYP27B1 causes VDDR1B (R-HSA-5579027)
  Vitamin D (calciferol) metabolism (R-HSA-196791)
• BioCyc Pathway: MetaCyc:HS17721-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
Vitamin D hydroxylation-deficient rickets, type 1B	DISLUITH	Strong	Autosomal recessive	[1]
Vitamin D-dependent rickets, type 1	DISBF2X7	Supportive	Autosomal recessive	[2]

1 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 Vitamin D 25-hydroxylase (CYP2R1).	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Vitamin D 25-hydroxylase (CYP2R1).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Vitamin D 25-hydroxylase (CYP2R1).	[5]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Vitamin D 25-hydroxylase (CYP2R1).	[6]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Vitamin D 25-hydroxylase (CYP2R1).	[7]
Obeticholic acid	DM3Q1SM	Approved	Obeticholic acid increases the expression of Vitamin D 25-hydroxylase (CYP2R1).	[8]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Vitamin D 25-hydroxylase (CYP2R1).	[9]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of Vitamin D 25-hydroxylase (CYP2R1).	[10]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Vitamin D 25-hydroxylase (CYP2R1).	[11]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Vitamin D 25-hydroxylase (CYP2R1).	[12]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Vitamin D 25-hydroxylase (CYP2R1).	[13]

References

• [1] Genetic evidence that the human CYP2R1 enzyme is a key vitamin D 25-hydroxylase. Proc Natl Acad Sci U S A. 2004 May 18;101(20):7711-5. doi: 10.1073/pnas.0402490101. Epub 2004 May 5.
• [2] Clinical Practice Guidelines for Rare Diseases: The Orphanet Database. PLoS One. 2017 Jan 18;12(1):e0170365. doi: 10.1371/journal.pone.0170365. eCollection 2017.
• [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] 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.
• [6] 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.
• [7] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [8] Pharmacotoxicology of clinically-relevant concentrations of obeticholic acid in an organotypic human hepatocyte system. Toxicol In Vitro. 2017 Mar;39:93-103.
• [9] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [10] Identification by automated screening of a small molecule that selectively eliminates neural stem cells derived from hESCs but not dopamine neurons. PLoS One. 2009 Sep 23;4(9):e7155.
• [11] 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.
• [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.