Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTTK98BH)

• DOT Name: 25-hydroxyvitamin D-1 alpha hydroxylase, mitochondrial (CYP27B1)
• Synonyms: EC 1.14.15.18; 25-OHD-1 alpha-hydroxylase; 25-hydroxyvitamin D(3) 1-alpha-hydroxylase; VD3 1A hydroxylase; Calcidiol 1-monooxygenase; Cytochrome P450 subfamily XXVIIB polypeptide 1; Cytochrome P450C1 alpha; Cytochrome P450VD1-alpha; Cytochrome p450 27B1
• Gene Name: CYP27B1
• Related Disease:
  Vitamin D-dependent rickets, type 1A
  Vitamin D-dependent rickets, type 1
• UniProt ID: CP27B_HUMAN
• EC Number: 1.14.15.18
• Pfam ID: PF00067
• Sequence:
  MTQTLKYASRVFHRVRWAPELGASLGYREYHSARRSLADIPGPSTPSFLAELFCKGGLSR
  LHELQVQGAAHFGPVWLASFGTVRTVYVAAPALVEELLRQEGPRPERCSFSPWTEHRRCR
  QRACGLLTAEGEEWQRLRSLLAPLLLRPQAAARYAGTLNNVVCDLVRRLRRQRGRGTGPP
  ALVRDVAGEFYKFGLEGIAAVLLGSRLGCLEAQVPPDTETFIRAVGSVFVSTLLTMAMPH
  WLRHLVPGPWGRLCRDWDQMFAFAQRHVERREAEAAMRNGGQPEKDLESGAHLTHFLFRE
  ELPAQSILGNVTELLLAGVDTVSNTLSWALYELSRHPEVQTALHSEITAALSPGSSAYPS
  ATVLSQLPLLKAVVKEVLRLYPVVPGNSRVPDKDIHVGDYIIPKNTLVTLCHYATSRDPA
  QFPEPNSFRPARWLGEGPTPHPFASLPFGFGKRSCMGRRLAELELQMALAQILTHFEVQP
  EPGAAPVRPKTRTVLVPERSINLQFLDR
• Function: A cytochrome P450 monooxygenase involved in vitamin D metabolism and in calcium and phosphorus homeostasis. Catalyzes the rate-limiting step in the activation of vitamin D in the kidney, namely the hydroxylation of 25-hydroxyvitamin D3/calcidiol at the C1alpha-position to form the hormonally active form of vitamin D3, 1alpha,25-dihydroxyvitamin D3/calcitriol that acts via the vitamin D receptor (VDR). Has 1alpha-hydroxylase activity on vitamin D intermediates of the CYP24A1-mediated inactivation pathway. Converts 24R,25-dihydroxyvitamin D3/secalciferol to 1-alpha,24,25-trihydroxyvitamin D3, an active ligand of VDR. Also active on 25-hydroxyvitamin D2. 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 FDXR/adrenodoxin reductase and FDX1/adrenodoxin.
• Tissue Specificity: Kidney.
• KEGG Pathway:
  Steroid biosynthesis (hsa00100)
  Metabolic pathways (hsa01100)
  Parathyroid hormone synthesis, secretion and action (hsa04928)
  Tuberculosis (hsa05152)
• Reactome Pathway:
  Vitamins (R-HSA-211916)
  Defective CYP27B1 causes VDDR1A (R-HSA-5579014)
  Vitamin D (calciferol) metabolism (R-HSA-196791)

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-dependent rickets, type 1A	DISMB8DW	Strong	Autosomal recessive	[1]
Vitamin D-dependent rickets, type 1	DISBF2X7	Supportive	Autosomal recessive	[2]

This DOT Affected the Biotransformations of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Calcitriol	DM8ZVJ7	Approved	25-hydroxyvitamin D-1 alpha hydroxylase, mitochondrial (CYP27B1) decreases the chemical synthesis of Calcitriol.	[20]
Calcidiol	DMN4CV5	Approved	25-hydroxyvitamin D-1 alpha hydroxylase, mitochondrial (CYP27B1) increases the hydroxylation of Calcidiol.	[21]

3 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 25-hydroxyvitamin D-1 alpha hydroxylase, mitochondrial (CYP27B1).	[3]
Arsenic	DMTL2Y1	Approved	Arsenic increases the methylation of 25-hydroxyvitamin D-1 alpha hydroxylase, mitochondrial (CYP27B1).	[8]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of 25-hydroxyvitamin D-1 alpha hydroxylase, mitochondrial (CYP27B1).	[18]

16 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 25-hydroxyvitamin D-1 alpha hydroxylase, mitochondrial (CYP27B1).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of 25-hydroxyvitamin D-1 alpha hydroxylase, mitochondrial (CYP27B1).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of 25-hydroxyvitamin D-1 alpha hydroxylase, mitochondrial (CYP27B1).	[6]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of 25-hydroxyvitamin D-1 alpha hydroxylase, mitochondrial (CYP27B1).	[7]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of 25-hydroxyvitamin D-1 alpha hydroxylase, mitochondrial (CYP27B1).	[9]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of 25-hydroxyvitamin D-1 alpha hydroxylase, mitochondrial (CYP27B1).	[10]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of 25-hydroxyvitamin D-1 alpha hydroxylase, mitochondrial (CYP27B1).	[11]
Etoposide	DMNH3PG	Approved	Etoposide increases the expression of 25-hydroxyvitamin D-1 alpha hydroxylase, mitochondrial (CYP27B1).	[6]
Malathion	DMXZ84M	Approved	Malathion increases the expression of 25-hydroxyvitamin D-1 alpha hydroxylase, mitochondrial (CYP27B1).	[12]
Melphalan	DMOLNHF	Approved	Melphalan increases the expression of 25-hydroxyvitamin D-1 alpha hydroxylase, mitochondrial (CYP27B1).	[13]
Sulfasalazine	DMICA9H	Approved	Sulfasalazine decreases the expression of 25-hydroxyvitamin D-1 alpha hydroxylase, mitochondrial (CYP27B1).	[14]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of 25-hydroxyvitamin D-1 alpha hydroxylase, mitochondrial (CYP27B1).	[15]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone affects the expression of 25-hydroxyvitamin D-1 alpha hydroxylase, mitochondrial (CYP27B1).	[16]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of 25-hydroxyvitamin D-1 alpha hydroxylase, mitochondrial (CYP27B1).	[17]
2-AMINO-1-METHYL-6-PHENYLIMIDAZO[4,5-B]PYRIDINE	DMNQL17	Investigative	2-AMINO-1-METHYL-6-PHENYLIMIDAZO[4,5-B]PYRIDINE decreases the expression of 25-hydroxyvitamin D-1 alpha hydroxylase, mitochondrial (CYP27B1).	[19]
biochanin A	DM0HPWY	Investigative	biochanin A increases the expression of 25-hydroxyvitamin D-1 alpha hydroxylase, mitochondrial (CYP27B1).	[17]

References

• [1] Vitamin D 1alpha-hydroxylase gene mutations in patients with 1alpha-hydroxylase deficiency. J Clin Endocrinol Metab. 2007 Aug;92(8):3177-82. doi: 10.1210/jc.2006-2664. Epub 2007 May 8.
• [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] Increased mitochondrial ROS formation by acetaminophen in human hepatic cells is associated with gene expression changes suggesting disruption of the mitochondrial electron transport chain. Toxicol Lett. 2015 Apr 16;234(2):139-50.
• [6] Differential regulation of vitamin D receptor (VDR) by the p53 Family: p73-dependent induction of VDR upon DNA damage. J Biol Chem. 2007 Oct 12;282(41):29847-54.
• [7] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [8] Association of Arsenic Exposure with Whole Blood DNA Methylation: An Epigenome-Wide Study of Bangladeshi Adults. Environ Health Perspect. 2019 May;127(5):57011. doi: 10.1289/EHP3849. Epub 2019 May 28.
• [9] 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.
• [10] 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.
• [11] Progesterone regulation of implantation-related genes: new insights into the role of oestrogen. Cell Mol Life Sci. 2007 Apr;64(7-8):1009-32.
• [12] Exposure to Insecticides Modifies Gene Expression and DNA Methylation in Hematopoietic Tissues In Vitro. Int J Mol Sci. 2023 Mar 26;24(7):6259. doi: 10.3390/ijms24076259.
• [13] Bone marrow osteoblast damage by chemotherapeutic agents. PLoS One. 2012;7(2):e30758. doi: 10.1371/journal.pone.0030758. Epub 2012 Feb 17.
• [14] Down-regulation by nuclear factor kappaB of human 25-hydroxyvitamin D3 1alpha-hydroxylase promoter. Mol Endocrinol. 2004 Oct;18(10):2440-50. doi: 10.1210/me.2002-0441. Epub 2004 Jul 8.
• [15] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [16] 25 hydroxy-vitamin D(3)-1alpha hydroxylase expression and activity in cultured human osteoblasts and their modulation by parathyroid hormone, estrogenic compounds and dihydrotestosterone. J Steroid Biochem Mol Biol. 2007 Nov-Dec;107(3-5):238-44. doi: 10.1016/j.jsbmb.2007.03.048. Epub 2007 Jun 27.
• [17] 25-Hydroxyvitamin D3-1alpha-hydroxylase is expressed in human vascular smooth muscle cells and is upregulated by parathyroid hormone and estrogenic compounds. Circulation. 2005 Apr 5;111(13):1666-71.
• [18] 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.
• [19] Preferential induction of the AhR gene battery in HepaRG cells after a single or repeated exposure to heterocyclic aromatic amines. Toxicol Appl Pharmacol. 2010 Nov 15;249(1):91-100.
• [20] [Vitamin D1alpha-hydroxylase deficiency as the cause of severe rickets in a 1-year-old-old boy]. Ugeskr Laeger. 2006 Feb 13;168(7):700-2.
• [21] Effects of 25-hydroxyvitamin D(3) on proliferation and osteoblast differentiation of human marrow stromal cells require CYP27B1/1alpha-hydroxylase. J Bone Miner Res. 2011 May;26(5):1145-53.