Details of Drug Off-Target (DOT)

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

DOT Name Steroid 17-alpha-hydroxylase/17,20 lyase (CYP17A1)
Synonyms EC 1.14.14.19; 17-alpha-hydroxyprogesterone aldolase; EC 1.14.14.32; CYPXVII; Cytochrome P450 17A1; Cytochrome P450-C17; Cytochrome P450c17; Steroid 17-alpha-monooxygenase
Gene Name CYP17A1
Related Disease
Congenital adrenal hyperplasia due to 17-alpha-hydroxylase deficiency ( )
Obsolete 46,XY disorder of sex development due to isolated 17,20-lyase deficiency ( )
UniProt ID
CP17A_HUMAN
3D Structure
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2D Sequence (FASTA)
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3D Structure (PDB)
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PDB ID
3RUK; 3SWZ; 4NKV; 4NKW; 4NKX; 4NKY; 4NKZ; 5IRQ; 5IRV; 5UYS; 6CHI; 6CIR; 6CIZ; 6WR0; 6WR1; 6WW0; 8FDA
EC Number
1.14.14.19; 1.14.14.32
Pfam ID
PF00067
Sequence
MWELVALLLLTLAYLFWPKRRCPGAKYPKSLLSLPLVGSLPFLPRHGHMHNNFFKLQKKY
GPIYSVRMGTKTTVIVGHHQLAKEVLIKKGKDFSGRPQMATLDIASNNRKGIAFADSGAH
WQLHRRLAMATFALFKDGDQKLEKIICQEISTLCDMLATHNGQSIDISFPVFVAVTNVIS
LICFNTSYKNGDPELNVIQNYNEGIIDNLSKDSLVDLVPWLKIFPNKTLEKLKSHVKIRN
DLLNKILENYKEKFRSDSITNMLDTLMQAKMNSDNGNAGPDQDSELLSDNHILTTIGDIF
GAGVETTTSVVKWTLAFLLHNPQVKKKLYEEIDQNVGFSRTPTISDRNRLLLLEATIREV
LRLRPVAPMLIPHKANVDSSIGEFAVDKGTEVIINLWALHHNEKEWHQPDQFMPERFLNP
AGTQLISPSVSYLPFGAGPRSCIGEILARQELFLIMAWLLQRFDLEVPDDGQLPSLEGIP
KVVFLIDSFKVKIKVRQAWREAQAEGST
Function
A cytochrome P450 monooxygenase involved in corticoid and androgen biosynthesis. Catalyzes 17-alpha hydroxylation of C21 steroids, which is common for both pathways. A second oxidative step, required only for androgen synthesis, involves an acyl-carbon cleavage. The 17-alpha hydroxy intermediates, as part of adrenal glucocorticoids biosynthesis pathway, are precursors of cortisol (Probable). Hydroxylates steroid hormones, pregnenolone and progesterone to form 17-alpha hydroxy metabolites, followed by the cleavage of the C17-C20 bond to form C19 steroids, dehydroepiandrosterone (DHEA) and androstenedione. Has 16-alpha hydroxylase activity. Catalyzes 16-alpha hydroxylation of 17-alpha hydroxy pregnenolone, followed by the cleavage of the C17-C20 bond to form 16-alpha-hydroxy DHEA. Also 16-alpha hydroxylates androgens, relevant for estriol synthesis. 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 )
Ovarian steroidogenesis (hsa04913 )
Prolactin sig.ling pathway (hsa04917 )
Cortisol synthesis and secretion (hsa04927 )
Cushing syndrome (hsa04934 )
Reactome Pathway
Glucocorticoid biosynthesis (R-HSA-194002 )
Defective CYP17A1 causes AH5 (R-HSA-5579028 )
Androgen biosynthesis (R-HSA-193048 )
BioCyc Pathway
MetaCyc:HS07560-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 17-alpha-hydroxylase deficiency DISWPTF5 Strong Autosomal recessive [1]
Obsolete 46,XY disorder of sex development due to isolated 17,20-lyase deficiency DIS5BTLG Supportive Autosomal recessive [2]
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Molecular Interaction Atlas (MIA) Jump to Detail Molecular Interaction Atlas of This DOT
This DOT Affected the Regulation of Drug Effects of 5 Drug(s)
Drug Name Drug ID Highest Status Interaction REF
Estradiol DMUNTE3 Approved Steroid 17-alpha-hydroxylase/17,20 lyase (CYP17A1) affects the metabolism of Estradiol. [35]
Arsenic DMTL2Y1 Approved Steroid 17-alpha-hydroxylase/17,20 lyase (CYP17A1) affects the metabolism of Arsenic. [36]
Estrone DM5T6US Approved Steroid 17-alpha-hydroxylase/17,20 lyase (CYP17A1) affects the abundance of Estrone. [38]
Corticotropin DMP9TWZ Approved Steroid 17-alpha-hydroxylase/17,20 lyase (CYP17A1) affects the abundance of Corticotropin. [39]
Hydroxyprogesterone DMIKQH5 Approved Steroid 17-alpha-hydroxylase/17,20 lyase (CYP17A1) increases the metabolism of Hydroxyprogesterone. [20]
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This DOT Affected the Biotransformations of 5 Drug(s)
Drug Name Drug ID Highest Status Interaction REF
Progesterone DMUY35B Approved Steroid 17-alpha-hydroxylase/17,20 lyase (CYP17A1) increases the hydroxylation of Progesterone. [37]
Pregnenolone DM6VFO1 Phase 4 Steroid 17-alpha-hydroxylase/17,20 lyase (CYP17A1) increases the hydroxylation of Pregnenolone. [40]
Androsterone DMITJAK Phase 3 Steroid 17-alpha-hydroxylase/17,20 lyase (CYP17A1) affects the chemical synthesis of Androsterone. [41]
ELTANOLONE DM38CIV Discontinued in Phase 3 Steroid 17-alpha-hydroxylase/17,20 lyase (CYP17A1) increases the hydroxylation of ELTANOLONE. [41]
17alpha-hydroxypregnenolone DMT2EPG Investigative Steroid 17-alpha-hydroxylase/17,20 lyase (CYP17A1) decreases the acetylation of 17alpha-hydroxypregnenolone. [37]
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47 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 17-alpha-hydroxylase/17,20 lyase (CYP17A1). [3]
Ciclosporin DMAZJFX Approved Ciclosporin decreases the expression of Steroid 17-alpha-hydroxylase/17,20 lyase (CYP17A1). [4]
Tretinoin DM49DUI Approved Tretinoin increases the expression of Steroid 17-alpha-hydroxylase/17,20 lyase (CYP17A1). [5]
Testosterone DM7HUNW Approved Testosterone decreases the expression of Steroid 17-alpha-hydroxylase/17,20 lyase (CYP17A1). [6]
Carbamazepine DMZOLBI Approved Carbamazepine decreases the expression of Steroid 17-alpha-hydroxylase/17,20 lyase (CYP17A1). [3]
Troglitazone DM3VFPD Approved Troglitazone decreases the activity of Steroid 17-alpha-hydroxylase/17,20 lyase (CYP17A1). [7]
Rosiglitazone DMILWZR Approved Rosiglitazone decreases the activity of Steroid 17-alpha-hydroxylase/17,20 lyase (CYP17A1). [7]
Nicotine DMWX5CO Approved Nicotine decreases the expression of Steroid 17-alpha-hydroxylase/17,20 lyase (CYP17A1). [8]
Pioglitazone DMKJ485 Approved Pioglitazone decreases the expression of Steroid 17-alpha-hydroxylase/17,20 lyase (CYP17A1). [9]
Dinoprostone DMTYOPD Approved Dinoprostone increases the expression of Steroid 17-alpha-hydroxylase/17,20 lyase (CYP17A1). [10]
Testosterone Undecanoate DMZO10Y Approved Testosterone Undecanoate decreases the expression of Steroid 17-alpha-hydroxylase/17,20 lyase (CYP17A1). [11]
Etretinate DM2CZFA Approved Etretinate increases the expression of Steroid 17-alpha-hydroxylase/17,20 lyase (CYP17A1). [12]
Aminoglutethimide DMWFHMZ Approved Aminoglutethimide decreases the expression of Steroid 17-alpha-hydroxylase/17,20 lyase (CYP17A1). [13]
Mitotane DMU1GX0 Approved Mitotane decreases the expression of Steroid 17-alpha-hydroxylase/17,20 lyase (CYP17A1). [14]
Clotrimazole DMMFCIH Approved Clotrimazole decreases the activity of Steroid 17-alpha-hydroxylase/17,20 lyase (CYP17A1). [15]
Prasterone DM67VKL Approved Prasterone decreases the expression of Steroid 17-alpha-hydroxylase/17,20 lyase (CYP17A1). [6]
Flurbiprofen DMGN4BY Approved Flurbiprofen decreases the activity of Steroid 17-alpha-hydroxylase/17,20 lyase (CYP17A1). [16]
Salbutamol DMN9CWF Approved Salbutamol increases the expression of Steroid 17-alpha-hydroxylase/17,20 lyase (CYP17A1). [17]
Lamotrigine DM8SXYG Approved Lamotrigine decreases the activity of Steroid 17-alpha-hydroxylase/17,20 lyase (CYP17A1). [18]
Miconazole DMPMYE8 Approved Miconazole decreases the activity of Steroid 17-alpha-hydroxylase/17,20 lyase (CYP17A1). [15]
Hydroxyflutamide DMGIZF5 Approved Hydroxyflutamide increases the expression of Steroid 17-alpha-hydroxylase/17,20 lyase (CYP17A1). [19]
Topiramate DM82Z30 Approved Topiramate decreases the activity of Steroid 17-alpha-hydroxylase/17,20 lyase (CYP17A1). [18]
Fluconazole DMOWZ6B Approved Fluconazole affects the activity of Steroid 17-alpha-hydroxylase/17,20 lyase (CYP17A1). [15]
Duloxetine DM9BI7M Approved Duloxetine decreases the activity of Steroid 17-alpha-hydroxylase/17,20 lyase (CYP17A1). [20]
FADROZOLE DM3C5GZ Approved FADROZOLE decreases the activity of Steroid 17-alpha-hydroxylase/17,20 lyase (CYP17A1). [21]
Tramadol DMRQD04 Approved Tramadol decreases the activity of Steroid 17-alpha-hydroxylase/17,20 lyase (CYP17A1). [20]
Levetiracetam DMTGDN8 Approved Levetiracetam decreases the expression of Steroid 17-alpha-hydroxylase/17,20 lyase (CYP17A1). [3]
ABIRATERONE DM8V75C Approved ABIRATERONE decreases the activity of Steroid 17-alpha-hydroxylase/17,20 lyase (CYP17A1). [22]
Pyruvic acid DM7Q41G Approved Pyruvic acid increases the expression of Steroid 17-alpha-hydroxylase/17,20 lyase (CYP17A1). [23]
Resveratrol DM3RWXL Phase 3 Resveratrol decreases the expression of Steroid 17-alpha-hydroxylase/17,20 lyase (CYP17A1). [24]
TOK-001 DMVJWPR Phase 2 TOK-001 decreases the activity of Steroid 17-alpha-hydroxylase/17,20 lyase (CYP17A1). [25]
Sphingosine-1-Phosphate DMJCQKA Phase 1 Sphingosine-1-Phosphate increases the expression of Steroid 17-alpha-hydroxylase/17,20 lyase (CYP17A1). [27]
Sphingosine DMO1FTI Phase 1 Sphingosine increases the expression of Steroid 17-alpha-hydroxylase/17,20 lyase (CYP17A1). [27]
Torcetrapib DMDHYM7 Discontinued in Phase 2 Torcetrapib increases the expression of Steroid 17-alpha-hydroxylase/17,20 lyase (CYP17A1). [28]
Antalarmin DM2EKX5 Terminated Antalarmin decreases the expression of Steroid 17-alpha-hydroxylase/17,20 lyase (CYP17A1). [29]
Bisphenol A DM2ZLD7 Investigative Bisphenol A decreases the expression of Steroid 17-alpha-hydroxylase/17,20 lyase (CYP17A1). [30]
Forskolin DM6ITNG Investigative Forskolin increases the expression of Steroid 17-alpha-hydroxylase/17,20 lyase (CYP17A1). [6]
PD98059 DMZC90M Investigative PD98059 increases the expression of Steroid 17-alpha-hydroxylase/17,20 lyase (CYP17A1). [9]
Piceatannol DMYOP45 Investigative Piceatannol decreases the activity of Steroid 17-alpha-hydroxylase/17,20 lyase (CYP17A1). [24]
2,6-Dihydroanthra/1,9-Cd/Pyrazol-6-One DMDN12L Investigative 2,6-Dihydroanthra/1,9-Cd/Pyrazol-6-One increases the expression of Steroid 17-alpha-hydroxylase/17,20 lyase (CYP17A1). [31]
Alpha-naphthoflavone DMELOIQ Investigative Alpha-naphthoflavone decreases the expression of Steroid 17-alpha-hydroxylase/17,20 lyase (CYP17A1). [32]
4-ANDROSTENE-3-17-DIONE DMSE8NU Investigative 4-ANDROSTENE-3-17-DIONE decreases the expression of Steroid 17-alpha-hydroxylase/17,20 lyase (CYP17A1). [6]
HPTE DMRPZD4 Investigative HPTE decreases the activity of Steroid 17-alpha-hydroxylase/17,20 lyase (CYP17A1). [33]
Cinnamic acid DM340FH Investigative Cinnamic acid decreases the activity of Steroid 17-alpha-hydroxylase/17,20 lyase (CYP17A1). [7]
1,2-dibromo-4-(1,2-dibromoethyl)cyclohexane DMDJYHK Investigative 1,2-dibromo-4-(1,2-dibromoethyl)cyclohexane increases the expression of Steroid 17-alpha-hydroxylase/17,20 lyase (CYP17A1). [19]
2-bromophenol DM6JDIY Investigative 2-bromophenol increases the expression of Steroid 17-alpha-hydroxylase/17,20 lyase (CYP17A1). [34]
astressin DMSFLTK Investigative astressin decreases the expression of Steroid 17-alpha-hydroxylase/17,20 lyase (CYP17A1). [29]
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⏷ Show the Full List of 47 Drug(s)
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 affects the methylation of Steroid 17-alpha-hydroxylase/17,20 lyase (CYP17A1). [26]
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References

1 17alpha-hydroxylase/17,20-lyase deficiency caused by a novel homozygous mutation (Y27Stop) in the cytochrome CYP17 gene. J Clin Endocrinol Metab. 2005 Jul;90(7):4362-5. doi: 10.1210/jc.2005-0136. Epub 2005 Apr 5.
2 Differential inhibition of 17alpha-hydroxylase and 17,20-lyase activities by three novel missense CYP17 mutations identified in patients with P450c17 deficiency. J Clin Endocrinol Metab. 2002 Dec;87(12):5714-21. doi: 10.1210/jc.2001-011880.
3 Differential effects of antiepileptic drugs on steroidogenesis in a human in vitro cell model. Acta Neurol Scand Suppl. 2009;(189):14-21.
4 Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
5 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.
6 Inhibition of CYP17 expression by adrenal androgens and transforming growth factor beta in adrenocortical cells. Acta Biochim Pol. 2004;51(4):907-17.
7 Cinnamic acid based thiazolidinediones inhibit human P450c17 and 3beta-hydroxysteroid dehydrogenase and improve insulin sensitivity independent of PPARgamma agonist activity. J Mol Endocrinol. 2004 Apr;32(2):425-36.
8 Prenatal nicotinic exposure suppresses fetal adrenal steroidogenesis via steroidogenic factor 1 (SF-1) deacetylation. Toxicol Appl Pharmacol. 2014 Jun 15;277(3):231-41.
9 Pioglitazone inhibits androgen production in NCI-H295R cells by regulating gene expression of CYP17 and HSD3B2. Mol Pharmacol. 2007 Mar;71(3):787-98.
10 Prostaglandin E2 via steroidogenic factor-1 coordinately regulates transcription of steroidogenic genes necessary for estrogen synthesis in endometriosis. J Clin Endocrinol Metab. 2009 Feb;94(2):623-31.
11 Levonorgestrel enhances spermatogenesis suppression by testosterone with greater alteration in testicular gene expression in men. Biol Reprod. 2009 Mar;80(3):484-92.
12 Retinoids and retinol differentially regulate steroid biosynthesis in ovarian theca cells isolated from normal cycling women and women with polycystic ovary syndrome. J Clin Endocrinol Metab. 2005 Aug;90(8):4858-65. doi: 10.1210/jc.2005-0330. Epub 2005 May 24.
13 The H295R system for evaluation of endocrine-disrupting effects. Ecotoxicol Environ Saf. 2006 Nov;65(3):293-305.
14 The effect of mitotane on viability, steroidogenesis and gene expression in NCI295R adrenocortical cells. Mol Med Rep. 2013 Mar;7(3):893-900.
15 The classic azole antifungal drugs are highly potent endocrine disruptors in vitro inhibiting steroidogenic CYP enzymes at concentrations lower than therapeutic Cmax. Toxicology. 2019 Sep 1;425:152247. doi: 10.1016/j.tox.2019.152247. Epub 2019 Jul 19.
16 Flurbiprofen inhibits androgen productions in rat immature leydig cells. Chem Res Toxicol. 2019 Aug 19;32(8):1504-1514.
17 Modulation of steroidogenic gene expression and hormone production of H295R cells by pharmaceuticals and other environmentally active compounds. Toxicol Appl Pharmacol. 2007 Dec 1;225(2):142-53.
18 Effects of anticonvulsants on human p450c17 (17alpha-hydroxylase/17,20 lyase) and 3beta-hydroxysteroid dehydrogenase type 2. Epilepsia. 2005 Mar;46(3):444-8.
19 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.
20 Steroidogenic disruptive effects of the serotonin-noradrenaline reuptake inhibitors duloxetine, venlafaxine and tramadol in the H295R cell assay and in a recombinant CYP17 assay. Toxicol In Vitro. 2018 Mar;47:63-71.
21 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.
22 A fission yeast-based test system for the determination of IC50 values of anti-prostate tumor drugs acting on CYP21. J Enzyme Inhib Med Chem. 2006 Oct;21(5):547-56.
23 Phosphorylation of CtBP1 by cAMP-dependent protein kinase modulates induction of CYP17 by stimulating partnering of CtBP1 and 2. J Biol Chem. 2008 Mar 14;283(11):6925-34. doi: 10.1074/jbc.M708432200. Epub 2008 Jan 9.
24 Inhibition of CYP17A1 activity by resveratrol, piceatannol, and synthetic resveratrol analogs. Prostate. 2014 Jun;74(8):839-51.
25 Novel C-17-heteroaryl steroidal CYP17 inhibitors/antiandrogens: synthesis, in vitro biological activity, pharmacokinetics, and antitumor activity in the LAPC4 human prostate cancer xenograft model. J Med Chem. 2005 Apr 21;48(8):2972-84.
26 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.
27 ACTH regulates steroidogenic gene expression and cortisol biosynthesis in the human adrenal cortex via sphingolipid metabolism. Endocr Res. 2004 Nov;30(4):787-94.
28 Steroid profiling in H295R cells to identify chemicals potentially disrupting the production of adrenal steroids. Toxicology. 2017 Apr 15;381:51-63.
29 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.
30 Effects of bisphenol analogues on steroidogenic gene expression and hormone synthesis in H295R cells. Chemosphere. 2016 Mar;147:9-19.
31 A role for FXR and human FGF-19 in the repression of paraoxonase-1 gene expression by bile acids. J Lipid Res. 2006 Feb;47(2):384-92.
32 Assessment of the potential of polyphenols as a CYP17 inhibitor free of adverse corticosteroid elevation. Biochem Pharmacol. 2014 Aug 1;90(3):288-96.
33 Effects of methoxychlor and its metabolite 2,2-bis(p-hydroxyphenyl)-1,1,1-trichloroethane on human and rat 17alpha-hydroxylase/17,20-lyase activity. Toxicol Lett. 2014 Mar 21;225(3):407-12.
34 Effects of brominated flame retardants and brominated dioxins on steroidogenesis in H295R human adrenocortical carcinoma cell line. Environ Toxicol Chem. 2007 Apr;26(4):764-72.
35 Variants in estrogen metabolism and biosynthesis genes and urinary estrogen metabolites in women with a family history of breast cancer. Breast Cancer Res Treat. 2007 Mar;102(1):111-7. doi: 10.1007/s10549-006-9308-7. Epub 2006 Jul 19.
36 Arsenic metabolism is influenced by polymorphisms in genes involved in one-carbon metabolism and reduction reactions. Mutat Res. 2009 Jul 10;667(1-2):4-14. doi: 10.1016/j.mrfmmm.2008.07.003. Epub 2008 Jul 17.
37 Functional characterization of mutant CYP17 genes isolated from a 17 alpha-hydroxylase/17,20-lyase-deficient patient. Metabolism. 2004 Dec;53(12):1527-31. doi: 10.1016/j.metabol.2004.05.018.
38 Bisphenol A disrupts steroidogenesis in human H295R cells. Toxicol Sci. 2011 Jun;121(2):320-7.
39 Partial 17alpha-hydroxylase/17,20-lyase deficiency-clinical report of five Chinese 46,XX cases. Gynecol Endocrinol. 2008 Jul;24(7):362-7. doi: 10.1080/09513590802194051.
40 17alpha-hydroxylase/17,20-Lyase deficiency due to novel compound heterozygote mutations: treatment for tall stature in a female with male pseudohermaphroditism and spontaneous puberty in her affected sister. J Pediatr Endocrinol Metab. 2005 Apr;18(4):403-11. doi: 10.1515/jpem.2005.18.4.403.
41 5alpha-reduced C21 steroids are substrates for human cytochrome P450c17. Arch Biochem Biophys. 2003 Oct 15;418(2):151-60. doi: 10.1016/j.abb.2003.07.003.