Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT6EBDHM)

• DOT Name: 17-beta-hydroxysteroid dehydrogenase type 1 (HSD17B1)
• Synonyms: 17-beta-HSD 1; EC 1.1.1.51; 20 alpha-hydroxysteroid dehydrogenase; 20-alpha-HSD; E2DH; Estradiol 17-beta-dehydrogenase 1; EC 1.1.1.62; Placental 17-beta-hydroxysteroid dehydrogenase; Short chain dehydrogenase/reductase family 28C member 1
• Gene Name: HSD17B1
• UniProt ID: DHB1_HUMAN
• PDB ID: 1A27; 1BHS; 1DHT; 1EQU; 1FDS; 1FDT; 1FDU; 1FDV; 1FDW; 1I5R; 1IOL; 1JTV; 1QYV; 1QYW; 1QYX; 3DEY; 3DHE; 3HB4; 3HB5; 3KLM; 3KLP; 3KM0; 6CGC; 6CGE; 6DTP; 6MNC; 6MNE; 7X3Z
• EC Number: 1.1.1.51; 1.1.1.62
• Pfam ID: PF00106
• Sequence:
  MARTVVLITGCSSGIGLHLAVRLASDPSQSFKVYATLRDLKTQGRLWEAARALACPPGSL
  ETLQLDVRDSKSVAAARERVTEGRVDVLVCNAGLGLLGPLEALGEDAVASVLDVNVVGTV
  RMLQAFLPDMKRRGSGRVLVTGSVGGLMGLPFNDVYCASKFALEGLCESLAVLLLPFGVH
  LSLIECGPVHTAFMEKVLGSPEEVLDRTDIHTFHRFYQYLAHSKQVFREAAQNPEEVAEV
  FLTALRAPKPTLRYFTTERFLPLLRMRLDDPSGSNYVTAMHREVFGDVPAKAEAGAEAGG
  GAGPGAEDEAGRGAVGDPELGDPPAAPQ
• Function: Favors the reduction of estrogens and androgens. Converts estrone (E1) to a more potent estrogen, 17beta-estradiol (E2). Also has 20-alpha-HSD activity. Uses preferentially NADH.
• KEGG Pathway:
  Steroid hormone biosynthesis (hsa00140)
  Metabolic pathways (hsa01100)
  Ovarian steroidogenesis (hsa04913)
• Reactome Pathway:
  The canonical retinoid cycle in rods (twilight vision) (R-HSA-2453902)
  Estrogen biosynthesis (R-HSA-193144)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Biotransformations of 3 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Estrone	DM5T6US	Approved	17-beta-hydroxysteroid dehydrogenase type 1 (HSD17B1) increases the chemical synthesis of Estrone.	[16]
Prasterone	DM67VKL	Approved	17-beta-hydroxysteroid dehydrogenase type 1 (HSD17B1) increases the chemical synthesis of Prasterone.	[16]
HE2100	DMCP2KH	Discontinued in Phase 1	17-beta-hydroxysteroid dehydrogenase type 1 (HSD17B1) increases the chemical synthesis of HE2100.	[16]

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 17-beta-hydroxysteroid dehydrogenase type 1 (HSD17B1).	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of 17-beta-hydroxysteroid dehydrogenase type 1 (HSD17B1).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of 17-beta-hydroxysteroid dehydrogenase type 1 (HSD17B1).	[3]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of 17-beta-hydroxysteroid dehydrogenase type 1 (HSD17B1).	[4]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol decreases the expression of 17-beta-hydroxysteroid dehydrogenase type 1 (HSD17B1).	[4]
Nicotine	DMWX5CO	Approved	Nicotine decreases the expression of 17-beta-hydroxysteroid dehydrogenase type 1 (HSD17B1).	[5]
Alitretinoin	DMME8LH	Approved	Alitretinoin increases the expression of 17-beta-hydroxysteroid dehydrogenase type 1 (HSD17B1).	[6]
Dutasteride	DMQ4TJK	Approved	Dutasteride increases the expression of 17-beta-hydroxysteroid dehydrogenase type 1 (HSD17B1).	[7]
Metyrapone	DMI7FVQ	Approved	Metyrapone decreases the expression of 17-beta-hydroxysteroid dehydrogenase type 1 (HSD17B1).	[8]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of 17-beta-hydroxysteroid dehydrogenase type 1 (HSD17B1).	[9]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the activity of 17-beta-hydroxysteroid dehydrogenase type 1 (HSD17B1).	[10]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of 17-beta-hydroxysteroid dehydrogenase type 1 (HSD17B1).	[11]
FORMESTANE	DMWIDJK	Withdrawn from market	FORMESTANE decreases the activity of 17-beta-hydroxysteroid dehydrogenase type 1 (HSD17B1).	[10]
LG100268	DM41RK2	Discontinued in Phase 1	LG100268 increases the expression of 17-beta-hydroxysteroid dehydrogenase type 1 (HSD17B1).	[6]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of 17-beta-hydroxysteroid dehydrogenase type 1 (HSD17B1).	[12]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of 17-beta-hydroxysteroid dehydrogenase type 1 (HSD17B1).	[13]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of 17-beta-hydroxysteroid dehydrogenase type 1 (HSD17B1).	[14]
Forskolin	DM6ITNG	Investigative	Forskolin increases the expression of 17-beta-hydroxysteroid dehydrogenase type 1 (HSD17B1).	[8]
Tributylstannanyl	DMHN7CB	Investigative	Tributylstannanyl increases the expression of 17-beta-hydroxysteroid dehydrogenase type 1 (HSD17B1).	[6]
2-bromophenol	DM6JDIY	Investigative	2-bromophenol increases the expression of 17-beta-hydroxysteroid dehydrogenase type 1 (HSD17B1).	[15]

References

• [1] 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.
• [2] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [3] Acetaminophen Modulates the Expression of Steroidogenesis-Associated Genes and Estradiol Levels in Human Placental JEG-3 Cells. Toxicol Sci. 2021 Jan 6;179(1):44-52. doi: 10.1093/toxsci/kfaa160.
• [4] Estrogenic endocrine disruptive components interfere with calcium handling and differentiation of human trophoblast cells. J Cell Biochem. 2003 Jul 1;89(4):755-70.
• [5] Decreased levels of H3K9ac and H3K27ac in the promotor region of ovarian P450 aromatase mediated low estradiol synthesis in female offspring rats induced by prenatal nicotine exposure as well as in human granulosa cells after nicotine treatment. Food Chem Toxicol. 2019 Jun;128:256-266. doi: 10.1016/j.fct.2019.03.055. Epub 2019 Apr 6.
• [6] Organotin compounds enhance 17beta-hydroxysteroid dehydrogenase type I activity in human choriocarcinoma JAr cells: potential promotion of 17beta-estradiol biosynthesis in human placenta. Biochem Pharmacol. 2006 Apr 28;71(9):1349-57.
• [7] Effects of dutasteride on the expression of genes related to androgen metabolism and related pathway in human prostate cancer cell lines. Invest New Drugs. 2007 Oct;25(5):491-7.
• [8] The H295R system for evaluation of endocrine-disrupting effects. Ecotoxicol Environ Saf. 2006 Nov;65(3):293-305.
• [9] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [10] Mammalian lignans and genistein decrease the activities of aromatase and 17beta-hydroxysteroid dehydrogenase in MCF-7 cells. J Steroid Biochem Mol Biol. 2005 Apr;94(5):461-7.
• [11] 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.
• [12] Effect of bisphenol A on human endometrial stromal fibroblasts in vitro. Reprod Biomed Online. 2011 Mar;22(3):249-56.
• [13] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [14] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
• [15] 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.
• [16] Steroid signalling in the ovarian surface epithelium. Trends Endocrinol Metab. 2005 Sep;16(7):327-33.