Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT45D396)

• DOT Name: 17-beta-hydroxysteroid dehydrogenase type 3 (HSD17B3)
• Synonyms: 17-beta-HSD 3; Estradiol 17-beta-dehydrogenase 2; EC 1.1.1.62; Short chain dehydrogenase/reductase family 12C member 2; Testicular 17-beta-hydroxysteroid dehydrogenase; Testosterone 17-beta-dehydrogenase 3; EC 1.1.1.64
• Gene Name: HSD17B3
• Related Disease: 46,XY disorder of sex development due to 17-beta-hydroxysteroid dehydrogenase 3 deficiency
• UniProt ID: DHB3_HUMAN
• EC Number: 1.1.1.62; 1.1.1.64
• Pfam ID: PF00106
• Sequence:
  MGDVLEQFFILTGLLVCLACLAKCVRFSRCVLLNYWKVLPKSFLRSMGQWAVITGAGDGI
  GKAYSFELAKRGLNVVLISRTLEKLEAIATEIERTTGRSVKIIQADFTKDDIYEHIKEKL
  AGLEIGILVNNVGMLPNLLPSHFLNAPDEIQSLIHCNITSVVKMTQLILKHMESRQKGLI
  LNISSGIALFPWPLYSMYSASKAFVCAFSKALQEEYKAKEVIIQVLTPYAVSTAMTKYLN
  TNVITKTADEFVKESLNYVTIGGETCGCLAHEILAGFLSLIPAWAFYSGAFQRLLLTHYV
  AYLKLNTKVR
• Function: Catalyzes the conversion of 17-oxosteroids to 17beta-hydroxysteroids. Favors the reduction of androstenedione to testosterone. Testosterone is the key androgen driving male development and function. Uses NADPH while the two other EDH17B enzymes use NADH. Androgens such as epiandrosterone, dehydroepiandrosterone, androsterone and androstanedione are accepted as substrates and reduced at C-17. Can reduce 11-ketoandrostenedione as well as 11beta-hydroxyandrostenedione at C-17 to the respective testosterone forms.
• Tissue Specificity: Testis.
• KEGG Pathway:
  Steroid hormone biosynthesis (hsa00140)
  Metabolic pathways (hsa01100)
• Reactome Pathway:
  Synthesis of very long-chain fatty acyl-CoAs (R-HSA-75876)
  Androgen biosynthesis (R-HSA-193048)
• BioCyc Pathway: MetaCyc:HS05461-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
46,XY disorder of sex development due to 17-beta-hydroxysteroid dehydrogenase 3 deficiency	DISR1LAL	Strong	Autosomal recessive	[1]

This DOT Affected the Biotransformations of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Testosterone	DM7HUNW	Approved	17-beta-hydroxysteroid dehydrogenase type 3 (HSD17B3) increases the chemical synthesis of Testosterone.	[10]

8 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 17-beta-hydroxysteroid dehydrogenase type 3 (HSD17B3).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of 17-beta-hydroxysteroid dehydrogenase type 3 (HSD17B3).	[3]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of 17-beta-hydroxysteroid dehydrogenase type 3 (HSD17B3).	[4]
Dutasteride	DMQ4TJK	Approved	Dutasteride increases the expression of 17-beta-hydroxysteroid dehydrogenase type 3 (HSD17B3).	[5]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of 17-beta-hydroxysteroid dehydrogenase type 3 (HSD17B3).	[6]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of 17-beta-hydroxysteroid dehydrogenase type 3 (HSD17B3).	[7]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of 17-beta-hydroxysteroid dehydrogenase type 3 (HSD17B3).	[8]
HPTE	DMRPZD4	Investigative	HPTE decreases the activity of 17-beta-hydroxysteroid dehydrogenase type 3 (HSD17B3).	[9]

References

• [1] A novel nonsense mutation in exon 1 of HSD17B3 gene in an Egyptian 46,XY adult female presenting with primary amenorrhea. Sex Dev. 2013;7(6):277-81. doi: 10.1159/000351822. Epub 2013 Jun 18.
• [2] 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.
• [3] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [4] Estradiol and selective estrogen receptor modulators differentially regulate target genes with estrogen receptors alpha and beta. Mol Biol Cell. 2004 Mar;15(3):1262-72. doi: 10.1091/mbc.e03-06-0360. Epub 2003 Dec 29.
• [5] 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.
• [6] 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.
• [7] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [8] The interference effects of bisphenol A on the synthesis of steroid hormones in human ovarian granulosa cells. Environ Toxicol. 2021 Apr;36(4):665-674. doi: 10.1002/tox.23070. Epub 2020 Dec 1.
• [9] Effects of methoxychlor and 2,2-bis(p-hydroxyphenyl)-1,1,1-trichloroethane on 3beta-hydroxysteroid dehydrogenase and 17beta-hydroxysteroid dehydrogenase-3 activities in human and rat testes. Int J Androl. 2011 Apr;34(2):138-44.
• [10] 17beta-hydroxysteroid dehydrogenase-3 deficiency: a rare endocrine cause of male-to-female sex reversal. Gynecol Endocrinol. 2006 Sep;22(9):488-94.