Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTN0UDVP)

• DOT Name: Steroid 21-hydroxylase (CYP21A2)
• Synonyms: EC 1.14.14.16; 21-OHase; Cytochrome P-450c21; Cytochrome P450 21; Cytochrome P450 XXI; Cytochrome P450-C21; Cytochrome P450-C21B
• Gene Name: CYP21A2
• Related Disease:
  Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency
  Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency, salt wasting form
  Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency, simple virilizing form
• UniProt ID: CP21A_HUMAN
• PDB ID: 4Y8W; 5VBU
• EC Number: 1.14.14.16
• Pfam ID: PF00067
• Sequence:
  MLLLGLLLLLPLLAGARLLWNWWKLRSLHLPPLAPGFLHLLQPDLPIYLLGLTQKFGPIY
  RLHLGLQDVVVLNSKRTIEEAMVKKWADFAGRPEPLTYKLVSRNYPDLSLGDYSLLWKAH
  KKLTRSALLLGIRDSMEPVVEQLTQEFCERMRAQPGTPVAIEEEFSLLTCSIICYLTFGD
  KIKDDNLMPAYYKCIQEVLKTWSHWSIQIVDVIPFLRFFPNPGLRRLKQAIEKRDHIVEM
  QLRQHKESLVAGQWRDMMDYMLQGVAQPSMEEGSGQLLEGHVHMAAVDLLIGGTETTANT
  LSWAVVFLLHHPEIQQRLQEELDHELGPGASSSRVPYKDRARLPLLNATIAEVLRLRPVV
  PLALPHRTTRPSSISGYDIPEGTVIIPNLQGAHLDETVWERPHEFWPDRFLEPGKNSRAL
  AFGCGARVCLGEPLARLELFVVLTRLLQAFTLLPSGDALPSLQPLPHCSVILKMQPFQVR
  LQPRGMGAHSPGQSQ
• Function: A cytochrome P450 monooxygenase that plays a major role in adrenal steroidogenesis. Catalyzes the hydroxylation at C-21 of progesterone and 17alpha-hydroxyprogesterone to respectively form 11-deoxycorticosterone and 11-deoxycortisol, intermediate metabolites in the biosynthetic pathway of mineralocorticoids and glucocorticoids. 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 cytochrome P450 reductase (CPR; NADPH-ferrihemoprotein reductase).
• KEGG Pathway:
  Steroid hormone biosynthesis (hsa00140)
  Metabolic pathways (hsa01100)
  Aldosterone synthesis and secretion (hsa04925)
  Cortisol synthesis and secretion (hsa04927)
  Cushing syndrome (hsa04934)
• Reactome Pathway:
  Glucocorticoid biosynthesis (R-HSA-194002)
  Endogenous sterols (R-HSA-211976)
  Defective CYP21A2 causes AH3 (R-HSA-5579021)
  Mineralocorticoid biosynthesis (R-HSA-193993)
• BioCyc Pathway: MetaCyc:HS09769-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency	DISMTRY0	Definitive	Autosomal recessive	[1]
Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency, salt wasting form	DISR735H	Supportive	Autosomal recessive	[2]
Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency, simple virilizing form	DISO2SE5	Supportive	Autosomal recessive	[2]

12 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 Steroid 21-hydroxylase (CYP21A2).	[3]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Steroid 21-hydroxylase (CYP21A2).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Steroid 21-hydroxylase (CYP21A2).	[5]
Obeticholic acid	DM3Q1SM	Approved	Obeticholic acid decreases the expression of Steroid 21-hydroxylase (CYP21A2).	[6]
Mitotane	DMU1GX0	Approved	Mitotane decreases the expression of Steroid 21-hydroxylase (CYP21A2).	[7]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Steroid 21-hydroxylase (CYP21A2).	[8]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the expression of Steroid 21-hydroxylase (CYP21A2).	[9]
Torcetrapib	DMDHYM7	Discontinued in Phase 2	Torcetrapib increases the expression of Steroid 21-hydroxylase (CYP21A2).	[11]
Forskolin	DM6ITNG	Investigative	Forskolin increases the expression of Steroid 21-hydroxylase (CYP21A2).	[12]
Tributylstannanyl	DMHN7CB	Investigative	Tributylstannanyl decreases the expression of Steroid 21-hydroxylase (CYP21A2).	[13]
Piceatannol	DMYOP45	Investigative	Piceatannol decreases the expression of Steroid 21-hydroxylase (CYP21A2).	[14]
3-MeSO2-DDE	DMAWEQH	Investigative	3-MeSO2-DDE decreases the expression of Steroid 21-hydroxylase (CYP21A2).	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Steroid 21-hydroxylase (CYP21A2).	[10]

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] 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] Differential effects of antiepileptic drugs on steroidogenesis in a human in vitro cell model. Acta Neurol Scand Suppl. 2009;(189):14-21.
• [4] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [5] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [6] Pharmacotoxicology of clinically-relevant concentrations of obeticholic acid in an organotypic human hepatocyte system. Toxicol In Vitro. 2017 Mar;39:93-103.
• [7] Mitotane exhibits dual effects on steroidogenic enzymes gene transcription under basal and cAMP-stimulating microenvironments in NCI-H295 cells. Toxicology. 2012 Aug 16;298(1-3):14-23.
• [8] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [9] Assessment of the potential of polyphenols as a CYP17 inhibitor free of adverse corticosteroid elevation. Biochem Pharmacol. 2014 Aug 1;90(3):288-96.
• [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] Steroid profiling in H295R cells to identify chemicals potentially disrupting the production of adrenal steroids. Toxicology. 2017 Apr 15;381:51-63.
• [12] The H295R system for evaluation of endocrine-disrupting effects. Ecotoxicol Environ Saf. 2006 Nov;65(3):293-305.
• [13] Organotin exposure stimulates steroidogenesis in H295R Cell via cAMP pathway. Ecotoxicol Environ Saf. 2018 Jul 30;156:148-153.
• [14] Inhibition of CYP17A1 activity by resveratrol, piceatannol, and synthetic resveratrol analogs. Prostate. 2014 Jun;74(8):839-51.
• [15] Biphasic hormonal responses to the adrenocorticolytic DDT metabolite 3-methylsulfonyl-DDE in human cells. Toxicol Appl Pharmacol. 2010 Feb 1;242(3):281-9.