Details of Drug Off-Target (DOT)

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

• DOT Name: Cytochrome P450 11B2, mitochondrial (CYP11B2)
• Synonyms: Aldosterone synthase; ALDOS; Aldosterone-synthesizing enzyme; CYPXIB2; Corticosterone 18-monooxygenase, CYP11B2; EC 1.14.15.5; Cytochrome P-450Aldo; Cytochrome P-450C18; Steroid 11-beta-hydroxylase, CYP11B2; EC 1.14.15.4; Steroid 18-hydroxylase
• Gene Name: CYP11B2
• Related Disease:
  Familial hyperreninemic hypoaldosteronism type 2
  Corticosterone methyloxidase type 2 deficiency
  Corticosterone methyloxidase type 1 deficiency
  Familial hypoaldosteronism
• UniProt ID: C11B2_HUMAN
• PDB ID: 4DVQ; 4FDH; 4ZGX; 6XZ8; 6XZ9; 7M8I; 7M8V
• EC Number: 1.14.15.4; 1.14.15.5
• Pfam ID: PF00067
• Sequence:
  MALRAKAEVCVAAPWLSLQRARALGTRAARAPRTVLPFEAMPQHPGNRWLRLLQIWREQG
  YEHLHLEMHQTFQELGPIFRYNLGGPRMVCVMLPEDVEKLQQVDSLHPCRMILEPWVAYR
  QHRGHKCGVFLLNGPEWRFNRLRLNPDVLSPKAVQRFLPMVDAVARDFSQALKKKVLQNA
  RGSLTLDVQPSIFHYTIEASNLALFGERLGLVGHSPSSASLNFLHALEVMFKSTVQLMFM
  PRSLSRWISPKVWKEHFEAWDCIFQYGDNCIQKIYQELAFNRPQHYTGIVAELLLKAELS
  LEAIKANSMELTAGSVDTTAFPLLMTLFELARNPDVQQILRQESLAAAASISEHPQKATT
  ELPLLRAALKETLRLYPVGLFLERVVSSDLVLQNYHIPAGTLVQVFLYSLGRNAALFPRP
  ERYNPQRWLDIRGSGRNFHHVPFGFGMRQCLGRRLAEAEMLLLLHHVLKHFLVETLTQED
  IKMVYSFILRPGTSPLLTFRAIN
• Function: A cytochrome P450 monooxygenase that catalyzes the biosynthesis of aldosterone, the main mineralocorticoid in the human body responsible for salt and water homeostasis, thus involved in blood pressure regulation, arterial hypertension, and the development of heart failure. Catalyzes three sequential oxidative reactions of 11-deoxycorticosterone (21-hydroxyprogesterone), namely 11-beta hydroxylation, followed by two successive oxidations at C18 yielding 18-hydroxy and then 18-oxo intermediates (that would not leave the enzyme active site during the consecutive hydroxylation reactions), ending with the formation of aldosterone. Can also produce 18-hydroxycortisol and 18-oxocortisol, derived from successive oxidations of cortisol at C18, normally found at very low levels, but significantly increased in primary aldosteronism, the most common form of secondary hypertension. 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). Could also be involved in the androgen metabolic pathway (Probable).
• Tissue Specificity: Expressed sporadically in the zona glomerulosa (zG) of the adrenal cortex (conventional zonation), as well as in aldosterone-producing cell clusters (APCCs) composed of morphological zG cells in contact with the capsule (variegated zonation).
• KEGG Pathway:
  Steroid hormone biosynthesis (hsa00140)
  Metabolic pathways (hsa01100)
  Aldosterone synthesis and secretion (hsa04925)
• Reactome Pathway:
  Glucocorticoid biosynthesis (R-HSA-194002)
  Endogenous sterols (R-HSA-211976)
  Defective CYP11B2 causes CMO-1 deficiency (R-HSA-5579009)
  Mineralocorticoid biosynthesis (R-HSA-193993)
• BioCyc Pathway: MetaCyc:HS11355-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Familial hyperreninemic hypoaldosteronism type 2	DIS7XTRD	Definitive	Autosomal recessive	[1]
Corticosterone methyloxidase type 2 deficiency	DISICD5B	Strong	Autosomal recessive	[2]
Corticosterone methyloxidase type 1 deficiency	DISMEWRE	Moderate	Autosomal recessive	[3]
Familial hypoaldosteronism	DISO4PCN	Supportive	Autosomal recessive	[4]

This DOT Affected the Biotransformations of 4 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Testosterone	DM7HUNW	Approved	Cytochrome P450 11B2, mitochondrial (CYP11B2) increases the chemical synthesis of Testosterone.	[21]
Aldosterone	DM9S2JW	Approved	Cytochrome P450 11B2, mitochondrial (CYP11B2) increases the chemical synthesis of Aldosterone.	[21]
(11-BETA)-11,21-DIHYDROXY-PREGN-4-ENE-3,20-DIONE	DMTPQ84	Investigative	Cytochrome P450 11B2, mitochondrial (CYP11B2) increases the chemical synthesis of (11-BETA)-11,21-DIHYDROXY-PREGN-4-ENE-3,20-DIONE.	[25]
Deoxycorticosterone	DMW6YLS	Investigative	Cytochrome P450 11B2, mitochondrial (CYP11B2) increases the hydroxylation of Deoxycorticosterone.	[25]

This DOT Affected the Drug Response of 4 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Benazepril	DMH1M9B	Approved	Cytochrome P450 11B2, mitochondrial (CYP11B2) affects the response to substance of Benazepril.	[22]
Candesartan	DMRK8OT	Approved	Cytochrome P450 11B2, mitochondrial (CYP11B2) affects the response to substance of Candesartan.	[23]
AMG 386	DMQJXL4	Phase 3	Cytochrome P450 11B2, mitochondrial (CYP11B2) affects the response to substance of AMG 386.	[24]
Irbesartan	DMTP1DC	Investigative	Cytochrome P450 11B2, mitochondrial (CYP11B2) increases the response to substance of Irbesartan.	[26]

1 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 11B2, mitochondrial (CYP11B2).	[5]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Carbamazepine	DMZOLBI	Approved	Carbamazepine increases the expression of Cytochrome P450 11B2, mitochondrial (CYP11B2).	[6]
Mitotane	DMU1GX0	Approved	Mitotane decreases the expression of Cytochrome P450 11B2, mitochondrial (CYP11B2).	[7]
Erythromycin	DM4K7GQ	Approved	Erythromycin increases the expression of Cytochrome P450 11B2, mitochondrial (CYP11B2).	[8]
Dutasteride	DMQ4TJK	Approved	Dutasteride increases the expression of Cytochrome P450 11B2, mitochondrial (CYP11B2).	[9]
Amoxicillin	DMUYNEI	Approved	Amoxicillin increases the expression of Cytochrome P450 11B2, mitochondrial (CYP11B2).	[8]
Potassium chloride	DMMTAJC	Approved	Potassium chloride increases the expression of Cytochrome P450 11B2, mitochondrial (CYP11B2).	[10]
FADROZOLE	DM3C5GZ	Approved	FADROZOLE decreases the activity of Cytochrome P450 11B2, mitochondrial (CYP11B2).	[11]
Dalcetrapib	DMKNCVM	Phase 3	Dalcetrapib increases the expression of Cytochrome P450 11B2, mitochondrial (CYP11B2).	[12]
Anacetrapib	DMP2BFG	Phase 3	Anacetrapib increases the expression of Cytochrome P450 11B2, mitochondrial (CYP11B2).	[12]
phorbol 12-myristate 13-acetate	DMJWD62	Phase 2	phorbol 12-myristate 13-acetate decreases the expression of Cytochrome P450 11B2, mitochondrial (CYP11B2).	[13]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Cytochrome P450 11B2, mitochondrial (CYP11B2).	[14]
Torcetrapib	DMDHYM7	Discontinued in Phase 2	Torcetrapib increases the expression of Cytochrome P450 11B2, mitochondrial (CYP11B2).	[15]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Cytochrome P450 11B2, mitochondrial (CYP11B2).	[16]
Forskolin	DM6ITNG	Investigative	Forskolin increases the expression of Cytochrome P450 11B2, mitochondrial (CYP11B2).	[17]
Tributylstannanyl	DMHN7CB	Investigative	Tributylstannanyl increases the expression of Cytochrome P450 11B2, mitochondrial (CYP11B2).	[18]
PD98059	DMZC90M	Investigative	PD98059 increases the expression of Cytochrome P450 11B2, mitochondrial (CYP11B2).	[13]
3-MeSO2-DDE	DMAWEQH	Investigative	3-MeSO2-DDE increases the expression of Cytochrome P450 11B2, mitochondrial (CYP11B2).	[19]
Bay K 8644	DMRWSGO	Investigative	Bay K 8644 increases the expression of Cytochrome P450 11B2, mitochondrial (CYP11B2).	[20]

References

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• [10] 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.
• [11] 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.
• [12] Cholesteryl ester-transfer protein inhibitors stimulate aldosterone biosynthesis in adipocytes through Nox-dependent processes. J Pharmacol Exp Ther. 2015 Apr;353(1):27-34.
• [13] On the control of the hCYP11B2 gene expressing cytochrome P450 aldosterone synthase. Endocr Res. 2004 Nov;30(4):807-12.
• [14] Transcriptional signatures of environmentally relevant exposures in normal human mammary epithelial cells: benzo[a]pyrene. Cancer Lett. 2005 Apr 28;221(2):201-11.
• [15] 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.
• [16] Effects of bisphenol analogues on steroidogenic gene expression and hormone synthesis in H295R cells. Chemosphere. 2016 Mar;147:9-19.
• [17] The H295R system for evaluation of endocrine-disrupting effects. Ecotoxicol Environ Saf. 2006 Nov;65(3):293-305.
• [18] Organotin exposure stimulates steroidogenesis in H295R Cell via cAMP pathway. Ecotoxicol Environ Saf. 2018 Jul 30;156:148-153.
• [19] Biphasic hormonal responses to the adrenocorticolytic DDT metabolite 3-methylsulfonyl-DDE in human cells. Toxicol Appl Pharmacol. 2010 Feb 1;242(3):281-9.
• [20] Angiotensin II and potassium regulate human CYP11B2 transcription through common cis-elements. Mol Endocrinol. 1997 May;11(5):638-49.
• [21] [Association study between a polymorphism of aldosterone synthetase gene and the pathogenesis of polycystic ovary syndrome]. Zhonghua Fu Chan Ke Za Zhi. 2003 Feb;38(2):94-7.
• [22] Associations between CYP11B2 gene polymorphisms and the response to angiotensin-converting enzyme inhibitors. Clin Pharmacol Ther. 2006 Jun;79(6):581-9. doi: 10.1016/j.clpt.2006.02.007.
• [23] Variants of the CYP11B2 gene predict response to therapy with candesartan. Eur J Pharmacol. 2002 Jun 7;445(1-2):151-2. doi: 10.1016/s0014-2999(02)01766-1.
• [24] Renin-angiotensin-aldosterone system and G-protein beta-3 subunit gene polymorphisms in salt-sensitive essential hypertension. J Hum Hypertens. 2003 Mar;17(3):187-91. doi: 10.1038/sj.jhh.1001534.
• [25] Fine-tuning the selectivity of aldosterone synthase inhibitors: structure-activity and structure-selectivity insights from studies of heteroaryl substituted 1,2,5,6-tetrahydropyrrolo[3,2,1-ij]quinolin-4-one derivatives. J Med Chem. 2011 Apr 14;54(7):2307-19.
• [26] Aldosterone synthase (CYP11B2) -344 C/T polymorphism is related to antihypertensive response: result from the Swedish Irbesartan Left Ventricular Hypertrophy Investigation versus Atenolol (SILVHIA) trial. Am J Hypertens. 2002 May;15(5):389-93. doi: 10.1016/s0895-7061(02)02256-2.