Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT0F2V2Z)

• DOT Name: Mineralocorticoid receptor (NR3C2)
• Synonyms: MR; Nuclear receptor subfamily 3 group C member 2
• Gene Name: NR3C2
• Related Disease:
  Autosomal dominant pseudohypoaldosteronism type 1
  Pseudohyperaldosteronism type 2
• UniProt ID: MCR_HUMAN
• PDB ID: 1Y9R; 1YA3; 2A3I; 2AA2; 2AA5; 2AA6; 2AA7; 2AAX; 2AB2; 2ABI; 2OAX; 3VHU; 3VHV; 3WFF; 3WFG; 4PF3; 4TNT; 4UDA; 4UDB; 5HCV; 5L7E; 5L7G; 5L7H; 5MWP; 5MWY; 6GEV; 6GG8; 6GGG; 6L88
• Pfam ID: PF00104 ; PF00105
• Sequence:
  METKGYHSLPEGLDMERRWGQVSQAVERSSLGPTERTDENNYMEIVNVSCVSGAIPNNST
  QGSSKEKQELLPCLQQDNNRPGILTSDIKTELESKELSATVAESMGLYMDSVRDADYSYE
  QQNQQGSMSPAKIYQNVEQLVKFYKGNGHRPSTLSCVNTPLRSFMSDSGSSVNGGVMRAV
  VKSPIMCHEKSPSVCSPLNMTSSVCSPAGINSVSSTTASFGSFPVHSPITQGTPLTCSPN
  VENRGSRSHSPAHASNVGSPLSSPLSSMKSSISSPPSHCSVKSPVSSPNNVTLRSSVSSP
  ANINNSRCSVSSPSNTNNRSTLSSPAASTVGSICSPVNNAFSYTASGTSAGSSTLRDVVP
  SPDTQEKGAQEVPFPKTEEVESAISNGVTGQLNIVQYIKPEPDGAFSSSCLGGNSKINSD
  SSFSVPIKQESTKHSCSGTSFKGNPTVNPFPFMDGSYFSFMDDKDYYSLSGILGPPVPGF
  DGNCEGSGFPVGIKQEPDDGSYYPEASIPSSAIVGVNSGGQSFHYRIGAQGTISLSRSAR
  DQSFQHLSSFPPVNTLVESWKSHGDLSSRRSDGYPVLEYIPENVSSSTLRSVSTGSSRPS
  KICLVCGDEASGCHYGVVTCGSCKVFFKRAVEGQHNYLCAGRNDCIIDKIRRKNCPACRL
  QKCLQAGMNLGARKSKKLGKLKGIHEEQPQQQQPPPPPPPPQSPEEGTTYIAPAKEPSVN
  TALVPQLSTISRALTPSPVMVLENIEPEIVYAGYDSSKPDTAENLLSTLNRLAGKQMIQV
  VKWAKVLPGFKNLPLEDQITLIQYSWMCLSSFALSWRSYKHTNSQFLYFAPDLVFNEEKM
  HQSAMYELCQGMHQISLQFVRLQLTFEEYTIMKVLLLLSTIPKDGLKSQAAFEEMRTNYI
  KELRKMVTKCPNNSGQSWQRFYQLTKLLDSMHDLVSDLLEFCFYTFRESHALKVEFPAML
  VEIISDQLPKVESGNAKPLYFHRK
• Function: Receptor for both mineralocorticoids (MC) such as aldosterone and glucocorticoids (GC) such as corticosterone or cortisol. Binds to mineralocorticoid response elements (MRE) and transactivates target genes. The effect of MC is to increase ion and water transport and thus raise extracellular fluid volume and blood pressure and lower potassium levels.
• Tissue Specificity: Ubiquitous. Highly expressed in distal tubules, convoluted tubules and cortical collecting duct in kidney, and in sweat glands. Detected at lower levels in cardiomyocytes, in epidermis and in colon enterocytes.
• KEGG Pathway: Aldosterone-regulated sodium reabsorption (hsa04960)
• Reactome Pathway:
  Nuclear Receptor transcription pathway (R-HSA-383280)
  SUMOylation of intracellular receptors (R-HSA-4090294)
  HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand (R-HSA-3371497)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autosomal dominant pseudohypoaldosteronism type 1	DIS4FXQ4	Definitive	Autosomal dominant	[1]
Pseudohyperaldosteronism type 2	DISU4CP9	Limited	Autosomal dominant	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Mineralocorticoid receptor (NR3C2) affects the response to substance of Arsenic.	[17]

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 Mineralocorticoid receptor (NR3C2).	[2]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Mineralocorticoid receptor (NR3C2).	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Mineralocorticoid receptor (NR3C2).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Mineralocorticoid receptor (NR3C2).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Mineralocorticoid receptor (NR3C2).	[5]
Carbamazepine	DMZOLBI	Approved	Carbamazepine increases the expression of Mineralocorticoid receptor (NR3C2).	[7]
Progesterone	DMUY35B	Approved	Progesterone increases the activity of Mineralocorticoid receptor (NR3C2).	[8]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Mineralocorticoid receptor (NR3C2).	[9]
Prednisolone	DMQ8FR2	Approved	Prednisolone increases the activity of Mineralocorticoid receptor (NR3C2).	[8]
Hydrocortisone	DMGEMB7	Approved	Hydrocortisone increases the activity of Mineralocorticoid receptor (NR3C2).	[8]
Budesonide	DMJIBAW	Approved	Budesonide increases the activity of Mineralocorticoid receptor (NR3C2).	[8]
Aldosterone	DM9S2JW	Approved	Aldosterone increases the expression of Mineralocorticoid receptor (NR3C2).	[10]
Spironolactone	DM2AQ5N	Approved	Spironolactone increases the activity of Mineralocorticoid receptor (NR3C2).	[11]
Betamethasone	DMAHJEF	Approved	Betamethasone increases the activity of Mineralocorticoid receptor (NR3C2).	[8]
Triamcinolone	DM98IXF	Approved	Triamcinolone decreases the activity of Mineralocorticoid receptor (NR3C2).	[8]
Cortisone	DMU5QZX	Approved	Cortisone increases the activity of Mineralocorticoid receptor (NR3C2).	[11]
Flumethasone	DMUNG4A	Approved	Flumethasone increases the activity of Mineralocorticoid receptor (NR3C2).	[8]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Mineralocorticoid receptor (NR3C2).	[12]
Beclomethasone dipropionate	DM5NW1E	Phase 4	Beclomethasone dipropionate increases the activity of Mineralocorticoid receptor (NR3C2).	[8]
Dalcetrapib	DMKNCVM	Phase 3	Dalcetrapib increases the expression of Mineralocorticoid receptor (NR3C2).	[13]
Anacetrapib	DMP2BFG	Phase 3	Anacetrapib increases the expression of Mineralocorticoid receptor (NR3C2).	[13]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Mineralocorticoid receptor (NR3C2).	[15]
Torcetrapib	DMDHYM7	Discontinued in Phase 2	Torcetrapib increases the expression of Mineralocorticoid receptor (NR3C2).	[13]

3 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Testosterone	DM7HUNW	Approved	Testosterone affects the binding of Mineralocorticoid receptor (NR3C2).	[6]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone affects the binding of Mineralocorticoid receptor (NR3C2).	[6]
(11-BETA)-11,21-DIHYDROXY-PREGN-4-ENE-3,20-DIONE	DMTPQ84	Investigative	(11-BETA)-11,21-DIHYDROXY-PREGN-4-ENE-3,20-DIONE affects the binding of Mineralocorticoid receptor (NR3C2).	[16]

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] 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.
• [3] 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.
• [4] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [5] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [6] The synthetic androgen methyltrienolone (r1881) acts as a potent antagonist of the mineralocorticoid receptor. Mol Pharmacol. 2007 Feb;71(2):473-82. doi: 10.1124/mol.106.031112. Epub 2006 Nov 14.
• [7] Transcriptional profiling of genes induced in the livers of patients treated with carbamazepine. Clin Pharmacol Ther. 2006 Nov;80(5):440-456.
• [8] Transactivation via the human glucocorticoid and mineralocorticoid receptor by therapeutically used steroids in CV-1 cells: a comparison of their glucocorticoid and mineralocorticoid properties. Eur J Endocrinol. 2004 Sep;151(3):397-406. doi: 10.1530/eje.0.1510397.
• [9] Dexamethasone controls aryl hydrocarbon receptor (AhR)-mediated CYP1A1 and CYP1A2 expression and activity in primary cultures of human hepatocytes. Chem Biol Interact. 2009 May 15;179(2-3):288-96.
• [10] Regulation of mineralocorticoid receptor expression during neuronal differentiation of murine embryonic stem cells. Endocrinology. 2010 May;151(5):2244-54. doi: 10.1210/en.2009-0753. Epub 2010 Mar 5.
• [11] The human mineralocorticoid receptor only partially differentiates between different ligands after expression in fission yeast. FEMS Yeast Res. 2005 Apr;5(6-7):627-33. doi: 10.1016/j.femsyr.2004.12.007.
• [12] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [13] Cholesteryl ester-transfer protein inhibitors stimulate aldosterone biosynthesis in adipocytes through Nox-dependent processes. J Pharmacol Exp Ther. 2015 Apr;353(1):27-34.
• [14] 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.
• [15] 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.
• [16] Structural and biochemical mechanisms for the specificity of hormone binding and coactivator assembly by mineralocorticoid receptor. Mol Cell. 2005 Aug 5;19(3):367-80. doi: 10.1016/j.molcel.2005.06.026.
• [17] Arsenic exposure, diabetes-related genes and diabetes prevalence in a general population from Spain. Environ Pollut. 2018 Apr;235:948-955. doi: 10.1016/j.envpol.2018.01.008. Epub 2018 Feb 21.