Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTKKL894)

• DOT Name: Cytochrome P450 11B1, mitochondrial (CYP11B1)
• Synonyms: CYP11B1; CYPXIB1; Cytochrome P-450c11; Cytochrome P450C11; Steroid 11-beta-hydroxylase, CYP11B1; EC 1.14.15.4
• Gene Name: CYP11B1
• Related Disease:
  Congenital adrenal hyperplasia due to 11-beta-hydroxylase deficiency
  Glucocorticoid-remediable aldosteronism
• UniProt ID: C11B1_HUMAN
• PDB ID: 6M7X; 7E7F
• EC Number: 1.14.15.4
• Pfam ID: PF00067
• Sequence:
  MALRAKAEVCMAVPWLSLQRAQALGTRAARVPRTVLPFEAMPRRPGNRWLRLLQIWREQG
  YEDLHLEVHQTFQELGPIFRYDLGGAGMVCVMLPEDVEKLQQVDSLHPHRMSLEPWVAYR
  QHRGHKCGVFLLNGPEWRFNRLRLNPEVLSPNAVQRFLPMVDAVARDFSQALKKKVLQNA
  RGSLTLDVQPSIFHYTIEASNLALFGERLGLVGHSPSSASLNFLHALEVMFKSTVQLMFM
  PRSLSRWTSPKVWKEHFEAWDCIFQYGDNCIQKIYQELAFSRPQQYTSIVAELLLNAELS
  PDAIKANSMELTAGSVDTTVFPLLMTLFELARNPNVQQALRQESLAAAASISEHPQKATT
  ELPLLRAALKETLRLYPVGLFLERVASSDLVLQNYHIPAGTLVRVFLYSLGRNPALFPRP
  ERYNPQRWLDIRGSGRNFYHVPFGFGMRQCLGRRLAEAEMLLLLHHVLKHLQVETLTQED
  IKMVYSFILRPSMFPLLTFRAIN
• Function: A cytochrome P450 monooxygenase involved in the biosynthesis of adrenal corticoids. Catalyzes a variety of reactions that are essential for many species, including detoxification, defense, and the formation of endogenous chemicals like steroid hormones. Steroid 11beta, 18- and 19-hydroxylase with preferred regioselectivity at 11beta, then 18, and lastly 19. Catalyzes the hydroxylation of 11-deoxycortisol and 11-deoxycorticosterone (21-hydroxyprogesterone) at 11beta position, yielding cortisol or corticosterone, respectively, but cannot produce aldosterone. Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate for hydroxylation 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). Due to its lack of 18-oxidation activity, it is incapable of generating aldosterone. Could also be involved in the androgen metabolic pathway (Probable).
• Tissue Specificity: Expressed in the zona fasciculata/reticularis of the adrenal cortex.
• KEGG Pathway:
  Steroid hormone biosynthesis (hsa00140)
  Metabolic pathways (hsa01100)
  Cortisol synthesis and secretion (hsa04927)
  Cushing syndrome (hsa04934)
• Reactome Pathway:
  Endogenous sterols (R-HSA-211976)
  Defective CYP11B1 causes AH4 (R-HSA-5579017)
  Glucocorticoid biosynthesis (R-HSA-194002)
• BioCyc Pathway: MetaCyc:HS08547-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 hyperplasia due to 11-beta-hydroxylase deficiency	DISBTYRN	Definitive	Autosomal recessive	[1]
Glucocorticoid-remediable aldosteronism	DIS0F683	Strong	Autosomal dominant	[2]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Cytochrome P450 11B1, mitochondrial (CYP11B1) increases the Renal function abnormal ADR of Acetaminophen.	[16]

This DOT Affected the Biotransformations of 3 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Hydrocortisone	DMGEMB7	Approved	Cytochrome P450 11B1, mitochondrial (CYP11B1) increases the chemical synthesis of Hydrocortisone.	[17]
(11-BETA)-11,21-DIHYDROXY-PREGN-4-ENE-3,20-DIONE	DMTPQ84	Investigative	Cytochrome P450 11B1, mitochondrial (CYP11B1) increases the chemical synthesis of (11-BETA)-11,21-DIHYDROXY-PREGN-4-ENE-3,20-DIONE.	[17]
Deoxycorticosterone	DMW6YLS	Investigative	Cytochrome P450 11B1, mitochondrial (CYP11B1) increases the chemical synthesis of Deoxycorticosterone.	[6]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Cytochrome P450 11B1, mitochondrial (CYP11B1).	[3]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Cytochrome P450 11B1, mitochondrial (CYP11B1).	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Cytochrome P450 11B1, mitochondrial (CYP11B1).	[4]
Ethanol	DMDRQZU	Approved	Ethanol decreases the expression of Cytochrome P450 11B1, mitochondrial (CYP11B1).	[5]
Mitotane	DMU1GX0	Approved	Mitotane increases the expression of Cytochrome P450 11B1, mitochondrial (CYP11B1).	[6]
Potassium chloride	DMMTAJC	Approved	Potassium chloride increases the expression of Cytochrome P450 11B1, mitochondrial (CYP11B1).	[7]
FADROZOLE	DM3C5GZ	Approved	FADROZOLE decreases the activity of Cytochrome P450 11B1, mitochondrial (CYP11B1).	[8]
Dalcetrapib	DMKNCVM	Phase 3	Dalcetrapib increases the expression of Cytochrome P450 11B1, mitochondrial (CYP11B1).	[9]
Anacetrapib	DMP2BFG	Phase 3	Anacetrapib increases the expression of Cytochrome P450 11B1, mitochondrial (CYP11B1).	[9]
Torcetrapib	DMDHYM7	Discontinued in Phase 2	Torcetrapib increases the expression of Cytochrome P450 11B1, mitochondrial (CYP11B1).	[11]
Tetramethylpyrazine	DMC0WNB	Discontinued in Phase 2	Tetramethylpyrazine increases the expression of Cytochrome P450 11B1, mitochondrial (CYP11B1).	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Cytochrome P450 11B1, mitochondrial (CYP11B1).	[13]
Forskolin	DM6ITNG	Investigative	Forskolin increases the expression of Cytochrome P450 11B1, mitochondrial (CYP11B1).	[14]
Tributylstannanyl	DMHN7CB	Investigative	Tributylstannanyl decreases the expression of Cytochrome P450 11B1, mitochondrial (CYP11B1).	[15]
Apigenin	DMI3491	Investigative	Apigenin decreases the expression of Cytochrome P450 11B1, mitochondrial (CYP11B1).	[4]
PD98059	DMZC90M	Investigative	PD98059 increases the expression of Cytochrome P450 11B1, mitochondrial (CYP11B1).	[4]
[3H]cAMP	DMZRQU7	Investigative	[3H]cAMP increases the expression of Cytochrome P450 11B1, mitochondrial (CYP11B1).	[4]
Alpha-naphthoflavone	DMELOIQ	Investigative	Alpha-naphthoflavone increases the expression of Cytochrome P450 11B1, mitochondrial (CYP11B1).	[4]
3-MeSO2-DDE	DMAWEQH	Investigative	3-MeSO2-DDE increases the expression of Cytochrome P450 11B1, mitochondrial (CYP11B1).	[6]

References

• [1] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [2] A chimaeric 11 beta-hydroxylase/aldosterone synthase gene causes glucocorticoid-remediable aldosteronism and human hypertension. Nature. 1992 Jan 16;355(6357):262-5. doi: 10.1038/355262a0.
• [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] Flavonoids exhibit diverse effects on CYP11B1 expression and cortisol synthesis. Toxicol Appl Pharmacol. 2012 Feb 1;258(3):343-50.
• [5] Autophagy as a compensation mechanism participates in ethanol-induced fetal adrenal dysfunction in female rats. Toxicol Appl Pharmacol. 2018 Apr 15;345:36-47.
• [6] Biphasic hormonal responses to the adrenocorticolytic DDT metabolite 3-methylsulfonyl-DDE in human cells. Toxicol Appl Pharmacol. 2010 Feb 1;242(3):281-9.
• [7] Blockade of T-type voltage-dependent Ca2+ channels by benidipine, a dihydropyridine calcium channel blocker, inhibits aldosterone production in human adrenocortical cell line NCI-H295R. Eur J Pharmacol. 2008 Apr 28;584(2-3):424-34. doi: 10.1016/j.ejphar.2008.02.001. Epub 2008 Feb 12.
• [8] Synthesis and evaluation of (pyridylmethylene)tetrahydronaphthalenes/-indanes and structurally modified derivatives: potent and selective inhibitors of aldosterone synthase. J Med Chem. 2005 Mar 10;48(5):1563-75.
• [9] Cholesteryl ester-transfer protein inhibitors stimulate aldosterone biosynthesis in adipocytes through Nox-dependent processes. J Pharmacol Exp Ther. 2015 Apr;353(1):27-34.
• [10] 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.
• [11] Torcetrapib induces aldosterone and cortisol production by an intracellular calcium-mediated mechanism independently of cholesteryl ester transfer protein inhibition. Endocrinology. 2009 May;150(5):2211-9.
• [12] Preparation of cardiovascular disease-related genes microarray and its application in exploring ligustrazine-induced changes in endothelial gene expression. Pol J Pharmacol. 2004 Jul-Aug;56(4):427-33.
• [13] Effects of bisphenol analogues on steroidogenic gene expression and hormone synthesis in H295R cells. Chemosphere. 2016 Mar;147:9-19.
• [14] 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.
• [15] Organotin exposure stimulates steroidogenesis in H295R Cell via cAMP pathway. Ecotoxicol Environ Saf. 2018 Jul 30;156:148-153.
• [16] ADReCS-Target: target profiles for aiding drug safety research and application. Nucleic Acids Res. 2018 Jan 4;46(D1):D911-D917. doi: 10.1093/nar/gkx899.
• [17] Steroid signalling in the ovarian surface epithelium. Trends Endocrinol Metab. 2005 Sep;16(7):327-33.