Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT2NV3AN)

• DOT Name: Cholesterol side-chain cleavage enzyme, mitochondrial (CYP11A1)
• Synonyms: EC 1.14.15.6; CYPXIA1; Cholesterol desmolase; Cytochrome P450 11A1; Cytochrome P450(scc)
• Gene Name: CYP11A1
• Related Disease:
  Congenital adrenal insuffiency with 46, XY sex reversal OR 46,XY disorder of sex development-adrenal insufficiency due to CYP11A1 deficiency
  Inherited isolated adrenal insufficiency due to partial CYP11A1 deficiency
• UniProt ID: CP11A_HUMAN
• PDB ID: 3N9Y; 3N9Z; 3NA0; 3NA1
• EC Number: 1.14.15.6
• Pfam ID: PF00067
• Sequence:
  MLAKGLPPRSVLVKGCQTFLSAPREGLGRLRVPTGEGAGISTRSPRPFNEIPSPGDNGWL
  NLYHFWRETGTHKVHLHHVQNFQKYGPIYREKLGNVESVYVIDPEDVALLFKSEGPNPER
  FLIPPWVAYHQYYQRPIGVLLKKSAAWKKDRVALNQEVMAPEATKNFLPLLDAVSRDFVS
  VLHRRIKKAGSGNYSGDISDDLFRFAFESITNVIFGERQGMLEEVVNPEAQRFIDAIYQM
  FHTSVPMLNLPPDLFRLFRTKTWKDHVAAWDVIFSKADIYTQNFYWELRQKGSVHHDYRG
  ILYRLLGDSKMSFEDIKANVTEMLAGGVDTTSMTLQWHLYEMARNLKVQDMLRAEVLAAR
  HQAQGDMATMLQLVPLLKASIKETLRLHPISVTLQRYLVNDLVLRDYMIPAKTLVQVAIY
  ALGREPTFFFDPENFDPTRWLSKDKNITYFRNLGFGWGVRQCLGRRIAELEMTIFLINML
  ENFRVEIQHLSDVGTTFNLILMPEKPISFTFWPFNQEATQQ
• Function: A cytochrome P450 monooxygenase that catalyzes the side-chain hydroxylation and cleavage of cholesterol to pregnenolone, the precursor of most steroid hormones. Catalyzes three sequential oxidation reactions of cholesterol, namely the hydroxylation at C22 followed with the hydroxylation at C20 to yield 20R,22R-hydroxycholesterol that is further cleaved between C20 and C22 to yield the C21-steroid pregnenolone and 4-methylpentanal. Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate and reducing the second into a water molecule. Two electrons are provided by NADPH via a two-protein mitochondrial transfer system comprising flavoprotein FDXR (adrenodoxin/ferredoxin reductase) and nonheme iron-sulfur protein FDX1 or FDX2 (adrenodoxin/ferredoxin).
• KEGG Pathway:
  Steroid hormone biosynthesis (hsa00140)
  Metabolic pathways (hsa01100)
  Ovarian steroidogenesis (hsa04913)
  Aldosterone synthesis and secretion (hsa04925)
  Cortisol synthesis and secretion (hsa04927)
  Cushing syndrome (hsa04934)
• Reactome Pathway:
  Endogenous sterols (R-HSA-211976)
  Defective CYP11A1 causes AICSR (R-HSA-5579026)
  Pregnenolone biosynthesis (R-HSA-196108)
• BioCyc Pathway: MetaCyc:HS06719-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
Congenital adrenal insuffiency with 46, XY sex reversal OR 46,XY disorder of sex development-adrenal insufficiency due to CYP11A1 deficiency	DISVAWTF	Strong	Autosomal recessive	[1]
Inherited isolated adrenal insufficiency due to partial CYP11A1 deficiency	DISEX5II	Supportive	Autosomal recessive	[2]

This DOT Affected the Regulation of Drug Effects of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Progesterone	DMUY35B	Approved	Cholesterol side-chain cleavage enzyme, mitochondrial (CYP11A1) affects the abundance of Progesterone.	[34]

This DOT Affected the Biotransformations of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Pregnenolone	DM6VFO1	Phase 4	Cholesterol side-chain cleavage enzyme, mitochondrial (CYP11A1) increases the chemical synthesis of Pregnenolone.	[35]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Cholesterol side-chain cleavage enzyme, mitochondrial (CYP11A1).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Cholesterol side-chain cleavage enzyme, mitochondrial (CYP11A1).	[4]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Cholesterol side-chain cleavage enzyme, mitochondrial (CYP11A1).	[5]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the expression of Cholesterol side-chain cleavage enzyme, mitochondrial (CYP11A1).	[7]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Cholesterol side-chain cleavage enzyme, mitochondrial (CYP11A1).	[8]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Cholesterol side-chain cleavage enzyme, mitochondrial (CYP11A1).	[9]
Carbamazepine	DMZOLBI	Approved	Carbamazepine decreases the expression of Cholesterol side-chain cleavage enzyme, mitochondrial (CYP11A1).	[10]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol decreases the expression of Cholesterol side-chain cleavage enzyme, mitochondrial (CYP11A1).	[5]
Ethanol	DMDRQZU	Approved	Ethanol decreases the expression of Cholesterol side-chain cleavage enzyme, mitochondrial (CYP11A1).	[11]
Nicotine	DMWX5CO	Approved	Nicotine decreases the expression of Cholesterol side-chain cleavage enzyme, mitochondrial (CYP11A1).	[12]
Lindane	DMB8CNL	Approved	Lindane decreases the expression of Cholesterol side-chain cleavage enzyme, mitochondrial (CYP11A1).	[13]
Vitamin C	DMXJ7O8	Approved	Vitamin C increases the expression of Cholesterol side-chain cleavage enzyme, mitochondrial (CYP11A1).	[14]
Hydrocortisone	DMGEMB7	Approved	Hydrocortisone decreases the expression of Cholesterol side-chain cleavage enzyme, mitochondrial (CYP11A1).	[15]
Dinoprostone	DMTYOPD	Approved	Dinoprostone increases the expression of Cholesterol side-chain cleavage enzyme, mitochondrial (CYP11A1).	[16]
Mitotane	DMU1GX0	Approved	Mitotane decreases the expression of Cholesterol side-chain cleavage enzyme, mitochondrial (CYP11A1).	[17]
Hydroxyflutamide	DMGIZF5	Approved	Hydroxyflutamide decreases the expression of Cholesterol side-chain cleavage enzyme, mitochondrial (CYP11A1).	[18]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Cholesterol side-chain cleavage enzyme, mitochondrial (CYP11A1).	[19]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Cholesterol side-chain cleavage enzyme, mitochondrial (CYP11A1).	[22]
Torcetrapib	DMDHYM7	Discontinued in Phase 2	Torcetrapib increases the expression of Cholesterol side-chain cleavage enzyme, mitochondrial (CYP11A1).	[23]
Antalarmin	DM2EKX5	Terminated	Antalarmin decreases the expression of Cholesterol side-chain cleavage enzyme, mitochondrial (CYP11A1).	[24]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Cholesterol side-chain cleavage enzyme, mitochondrial (CYP11A1).	[26]
Forskolin	DM6ITNG	Investigative	Forskolin increases the expression of Cholesterol side-chain cleavage enzyme, mitochondrial (CYP11A1).	[27]
U0126	DM31OGF	Investigative	U0126 increases the expression of Cholesterol side-chain cleavage enzyme, mitochondrial (CYP11A1).	[28]
Dibutyl phthalate	DMEDGKO	Investigative	Dibutyl phthalate decreases the expression of Cholesterol side-chain cleavage enzyme, mitochondrial (CYP11A1).	[29]
GW-3965	DMG60ET	Investigative	GW-3965 decreases the expression of Cholesterol side-chain cleavage enzyme, mitochondrial (CYP11A1).	[30]
[3H]cAMP	DMZRQU7	Investigative	[3H]cAMP increases the expression of Cholesterol side-chain cleavage enzyme, mitochondrial (CYP11A1).	[28]
Piceatannol	DMYOP45	Investigative	Piceatannol decreases the expression of Cholesterol side-chain cleavage enzyme, mitochondrial (CYP11A1).	[31]
1,2-dibromo-4-(1,2-dibromoethyl)cyclohexane	DMDJYHK	Investigative	1,2-dibromo-4-(1,2-dibromoethyl)cyclohexane increases the expression of Cholesterol side-chain cleavage enzyme, mitochondrial (CYP11A1).	[18]
G6976	DMEZO4M	Investigative	G6976 increases the expression of Cholesterol side-chain cleavage enzyme, mitochondrial (CYP11A1).	[32]
2-bromophenol	DM6JDIY	Investigative	2-bromophenol increases the expression of Cholesterol side-chain cleavage enzyme, mitochondrial (CYP11A1).	[33]
astressin	DMSFLTK	Investigative	astressin decreases the expression of Cholesterol side-chain cleavage enzyme, mitochondrial (CYP11A1).	[24]

4 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 side-chain cleavage enzyme, mitochondrial (CYP11A1).	[6]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the acetylation of Cholesterol side-chain cleavage enzyme, mitochondrial (CYP11A1).	[20]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Cholesterol side-chain cleavage enzyme, mitochondrial (CYP11A1).	[21]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Cholesterol side-chain cleavage enzyme, mitochondrial (CYP11A1).	[25]

References

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• [2] A novel entity of clinically isolated adrenal insufficiency caused by a partially inactivating mutation of the gene encoding for P450 side chain cleavage enzyme (CYP11A1). J Clin Endocrinol Metab. 2011 Nov;96(11):E1798-806. doi: 10.1210/jc.2011-1277. Epub 2011 Aug 31.
• [3] Differential effects of antiepileptic drugs on steroidogenesis in a human in vitro cell model. Acta Neurol Scand Suppl. 2009;(189):14-21.
• [4] Use of organ culture to study the human fetal testis development: effect of retinoic acid. J Clin Endocrinol Metab. 2006 Jul;91(7):2696-703.
• [5] Estrogenic endocrine disruptive components interfere with calcium handling and differentiation of human trophoblast cells. J Cell Biochem. 2003 Jul 1;89(4):755-70.
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• [7] MS4A3-HSP27 target pathway reveals potential for haematopoietic disorder treatment in alimentary toxic aleukia. Cell Biol Toxicol. 2023 Feb;39(1):201-216. doi: 10.1007/s10565-021-09639-4. Epub 2021 Sep 28.
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• [12] Nicotine induced CpG methylation of Pax6 binding motif in StAR promoter reduces the gene expression and cortisol production. Toxicol Appl Pharmacol. 2011 Dec 15;257(3):328-37.
• [13] Steroidogenic gene expression in H295R cells and the human adrenal gland: adrenotoxic effects of lindane in vitro. J Appl Toxicol. 2006 Nov-Dec;26(6):484-92.
• [14] Ascorbic acid transported by sodium-dependent vitamin C transporter 2 stimulates steroidogenesis in human choriocarcinoma cells. Endocrinology. 2008 Jan;149(1):73-83.
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• [18] Androgen receptor modulation following combination exposure to brominated flame-retardants. Sci Rep. 2018 Mar 19;8(1):4843. doi: 10.1038/s41598-018-23181-0.
• [19] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [20] Resveratrol stimulates cortisol biosynthesis by activating SIRT-dependent deacetylation of P450scc. Endocrinology. 2012 Jul;153(7):3258-68.
• [21] 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.
• [22] 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.
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• [24] Corticotropin-releasing hormone (CRH) and urocortin act through type 1 CRH receptors to stimulate dehydroepiandrosterone sulfate production in human fetal adrenal cells. J Clin Endocrinol Metab. 2005 Sep;90(9):5393-400.
• [25] 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.
• [26] Regulation of chromatin assembly and cell transformation by formaldehyde exposure in human cells. Environ Health Perspect. 2017 Sep 21;125(9):097019.
• [27] A benzimidazole fungicide, benomyl, and its metabolite, carbendazim, induce aromatase activity in a human ovarian granulose-like tumor cell line (KGN). Endocrinology. 2004 Apr;145(4):1860-9.
• [28] Low-dose bisphenol A activates the ERK signaling pathway and attenuates steroidogenic gene expression in human placental cells. Biol Reprod. 2018 Feb 1;98(2):250-258.
• [29] Dibutyl phthalate impairs steroidogenesis and a subset of LH-dependent genes in cultured human mural granulosa cell in vitro. Reprod Toxicol. 2017 Apr;69:13-18.
• [30] Inhibition of progesterone production in human luteinized granulosa cells treated with LXR agonists. Mol Hum Reprod. 2007 Jun;13(6):373-9.
• [31] Inhibition of CYP17A1 activity by resveratrol, piceatannol, and synthetic resveratrol analogs. Prostate. 2014 Jun;74(8):839-51.
• [32] Corticotropin-releasing hormone inhibits progesterone production in cultured human placental trophoblasts. J Mol Endocrinol. 2006 Dec;37(3):533-40.
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• [35] Steroid signalling in the ovarian surface epithelium. Trends Endocrinol Metab. 2005 Sep;16(7):327-33.