Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT02MSKN)

• DOT Name: 3 beta-hydroxysteroid dehydrogenase/Delta 5-->4-isomerase type 2 (HSD3B2)
• Synonyms: 3 beta-hydroxysteroid dehydrogenase/Delta 5-->4-isomerase type II; 3-beta-HSD II; 3-beta-HSD adrenal and gonadal type
• Gene Name: HSD3B2
• Related Disease: Congenital adrenal hyperplasia due to 3-beta-hydroxysteroid dehydrogenase deficiency
• UniProt ID: 3BHS2_HUMAN
• EC Number: 1.1.1.145; 5.3.3.1
• Pfam ID: PF01073
• Sequence:
  MGWSCLVTGAGGLLGQRIVRLLVEEKELKEIRALDKAFRPELREEFSKLQNRTKLTVLEG
  DILDEPFLKRACQDVSVVIHTACIIDVFGVTHRESIMNVNVKGTQLLLEACVQASVPVFI
  YTSSIEVAGPNSYKEIIQNGHEEEPLENTWPTPYPYSKKLAEKAVLAANGWNLKNGDTLY
  TCALRPTYIYGEGGPFLSASINEALNNNGILSSVGKFSTVNPVYVGNVAWAHILALRALR
  DPKKAPSVRGQFYYISDDTPHQSYDNLNYILSKEFGLRLDSRWSLPLTLMYWIGFLLEVV
  SFLLSPIYSYQPPFNRHTVTLSNSVFTFSYKKAQRDLAYKPLYSWEEAKQKTVEWVGSLV
  DRHKETLKSKTQ
• Function: 3-beta-HSD is a bifunctional enzyme, that catalyzes the oxidative conversion of Delta(5)-ene-3-beta-hydroxy steroid, and the oxidative conversion of ketosteroids. The 3-beta-HSD enzymatic system plays a crucial role in the biosynthesis of all classes of hormonal steroids.
• Tissue Specificity: Expressed in adrenal gland, testis and ovary.
• KEGG Pathway:
  Steroid hormone biosynthesis (hsa00140)
  Metabolic pathways (hsa01100)
  Ovarian steroidogenesis (hsa04913)
  Aldosterone synthesis and secretion (hsa04925)
  Cortisol synthesis and secretion (hsa04927)
  Cushing syndrome (hsa04934)
• Reactome Pathway:
  Mineralocorticoid biosynthesis (R-HSA-193993)
  Glucocorticoid biosynthesis (R-HSA-194002)
  Androgen biosynthesis (R-HSA-193048)
• BioCyc Pathway: MetaCyc:HS10943-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Congenital adrenal hyperplasia due to 3-beta-hydroxysteroid dehydrogenase deficiency	DIS7E98M	Strong	Autosomal recessive	[1]

24 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 3 beta-hydroxysteroid dehydrogenase/Delta 5-->4-isomerase type 2 (HSD3B2).	[2]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of 3 beta-hydroxysteroid dehydrogenase/Delta 5-->4-isomerase type 2 (HSD3B2).	[3]
Carbamazepine	DMZOLBI	Approved	Carbamazepine decreases the activity of 3 beta-hydroxysteroid dehydrogenase/Delta 5-->4-isomerase type 2 (HSD3B2).	[4]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of 3 beta-hydroxysteroid dehydrogenase/Delta 5-->4-isomerase type 2 (HSD3B2).	[5]
Troglitazone	DM3VFPD	Approved	Troglitazone decreases the activity of 3 beta-hydroxysteroid dehydrogenase/Delta 5-->4-isomerase type 2 (HSD3B2).	[6]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone decreases the activity of 3 beta-hydroxysteroid dehydrogenase/Delta 5-->4-isomerase type 2 (HSD3B2).	[6]
Pioglitazone	DMKJ485	Approved	Pioglitazone decreases the expression of 3 beta-hydroxysteroid dehydrogenase/Delta 5-->4-isomerase type 2 (HSD3B2).	[7]
Lindane	DMB8CNL	Approved	Lindane decreases the expression of 3 beta-hydroxysteroid dehydrogenase/Delta 5-->4-isomerase type 2 (HSD3B2).	[8]
Dinoprostone	DMTYOPD	Approved	Dinoprostone increases the expression of 3 beta-hydroxysteroid dehydrogenase/Delta 5-->4-isomerase type 2 (HSD3B2).	[9]
Mitotane	DMU1GX0	Approved	Mitotane decreases the expression of 3 beta-hydroxysteroid dehydrogenase/Delta 5-->4-isomerase type 2 (HSD3B2).	[10]
Lamotrigine	DM8SXYG	Approved	Lamotrigine decreases the activity of 3 beta-hydroxysteroid dehydrogenase/Delta 5-->4-isomerase type 2 (HSD3B2).	[4]
Topiramate	DM82Z30	Approved	Topiramate decreases the activity of 3 beta-hydroxysteroid dehydrogenase/Delta 5-->4-isomerase type 2 (HSD3B2).	[4]
Metyrapone	DMI7FVQ	Approved	Metyrapone decreases the expression of 3 beta-hydroxysteroid dehydrogenase/Delta 5-->4-isomerase type 2 (HSD3B2).	[11]
Levetiracetam	DMTGDN8	Approved	Levetiracetam decreases the expression of 3 beta-hydroxysteroid dehydrogenase/Delta 5-->4-isomerase type 2 (HSD3B2).	[2]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of 3 beta-hydroxysteroid dehydrogenase/Delta 5-->4-isomerase type 2 (HSD3B2).	[12]
Torcetrapib	DMDHYM7	Discontinued in Phase 2	Torcetrapib increases the expression of 3 beta-hydroxysteroid dehydrogenase/Delta 5-->4-isomerase type 2 (HSD3B2).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of 3 beta-hydroxysteroid dehydrogenase/Delta 5-->4-isomerase type 2 (HSD3B2).	[15]
Forskolin	DM6ITNG	Investigative	Forskolin increases the expression of 3 beta-hydroxysteroid dehydrogenase/Delta 5-->4-isomerase type 2 (HSD3B2).	[11]
Tributylstannanyl	DMHN7CB	Investigative	Tributylstannanyl decreases the expression of 3 beta-hydroxysteroid dehydrogenase/Delta 5-->4-isomerase type 2 (HSD3B2).	[16]
PD98059	DMZC90M	Investigative	PD98059 increases the expression of 3 beta-hydroxysteroid dehydrogenase/Delta 5-->4-isomerase type 2 (HSD3B2).	[7]
[3H]cAMP	DMZRQU7	Investigative	[3H]cAMP increases the expression of 3 beta-hydroxysteroid dehydrogenase/Delta 5-->4-isomerase type 2 (HSD3B2).	[17]
Piceatannol	DMYOP45	Investigative	Piceatannol decreases the expression of 3 beta-hydroxysteroid dehydrogenase/Delta 5-->4-isomerase type 2 (HSD3B2).	[18]
Cinnamic acid	DM340FH	Investigative	Cinnamic acid decreases the activity of 3 beta-hydroxysteroid dehydrogenase/Delta 5-->4-isomerase type 2 (HSD3B2).	[6]
2-bromophenol	DM6JDIY	Investigative	2-bromophenol increases the expression of 3 beta-hydroxysteroid dehydrogenase/Delta 5-->4-isomerase type 2 (HSD3B2).	[19]

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 increases the methylation of 3 beta-hydroxysteroid dehydrogenase/Delta 5-->4-isomerase type 2 (HSD3B2).	[13]

References

• [1] A new insight into the molecular basis of 3beta-hydroxysteroid dehydrogenase deficiency. Endocr Res. 2000 Nov;26(4):761-70. doi: 10.3109/07435800009048597.
• [2] Differential effects of antiepileptic drugs on steroidogenesis in a human in vitro cell model. Acta Neurol Scand Suppl. 2009;(189):14-21.
• [3] 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.
• [4] Effects of anticonvulsants on human p450c17 (17alpha-hydroxylase/17,20 lyase) and 3beta-hydroxysteroid dehydrogenase type 2. Epilepsia. 2005 Mar;46(3):444-8.
• [5] Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
• [6] 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.
• [7] Pioglitazone inhibits androgen production in NCI-H295R cells by regulating gene expression of CYP17 and HSD3B2. Mol Pharmacol. 2007 Mar;71(3):787-98.
• [8] 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.
• [9] 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.
• [10] Biphasic hormonal responses to the adrenocorticolytic DDT metabolite 3-methylsulfonyl-DDE in human cells. Toxicol Appl Pharmacol. 2010 Feb 1;242(3):281-9.
• [11] The H295R system for evaluation of endocrine-disrupting effects. Ecotoxicol Environ Saf. 2006 Nov;65(3):293-305.
• [12] 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.
• [13] 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.
• [14] Steroid profiling in H295R cells to identify chemicals potentially disrupting the production of adrenal steroids. Toxicology. 2017 Apr 15;381:51-63.
• [15] Effects of bisphenol analogues on steroidogenic gene expression and hormone synthesis in H295R cells. Chemosphere. 2016 Mar;147:9-19.
• [16] Organotin exposure stimulates steroidogenesis in H295R Cell via cAMP pathway. Ecotoxicol Environ Saf. 2018 Jul 30;156:148-153.
• [17] Inhibitory effects of cholesterol sulfate on progesterone production in human granulosa-like tumor cell line, KGN. Endocr J. 2008 Jul;55(3):575-81.
• [18] Inhibition of CYP17A1 activity by resveratrol, piceatannol, and synthetic resveratrol analogs. Prostate. 2014 Jun;74(8):839-51.
• [19] 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.