Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT2Y9IW4)

• DOT Name: 3 beta-hydroxysteroid dehydrogenase type 7 (HSD3B7)
• Synonyms: 3 beta-hydroxysteroid dehydrogenase type VII; 3-beta-HSD VII; 3-beta-hydroxy-Delta(5)-C27 steroid oxidoreductase; C(27) 3-beta-HSD; EC 1.1.1.-; Cholest-5-ene-3-beta,7-alpha-diol 3-beta-dehydrogenase; EC 1.1.1.181
• Gene Name: HSD3B7
• Related Disease:
  Cholestasis
  Congenital bile acid synthesis defect 1
  Neoplasm
  Progressive familial intrahepatic cholestasis type 1
  Progressive familial intrahepatic cholestasis
• UniProt ID: 3BHS7_HUMAN
• EC Number: 1.1.1.-; 1.1.1.181
• Pfam ID: PF01073
• Sequence:
  MADSAQAQKLVYLVTGGCGFLGEHVVRMLLQREPRLGELRVFDQHLGPWLEELKTGPVRV
  TAIQGDVTQAHEVAAAVAGAHVVIHTAGLVDVFGRASPKTIHEVNVQGTRNVIEACVQTG
  TRFLVYTSSMEVVGPNTKGHPFYRGNEDTPYEAVHRHPYPCSKALAEWLVLEANGRKVRG
  GLPLVTCALRPTGIYGEGHQIMRDFYRQGLRLGGWLFRAIPASVEHGRVYVGNVAWMHVL
  AARELEQRATLMGGQVYFCYDGSPYRSYEDFNMEFLGPCGLRLVGARPLLPYWLLVFLAA
  LNALLQWLLRPLVLYAPLLNPYTLAVANTTFTVSTDKAQRHFGYEPLFSWEDSRTRTILW
  VQAATGSAQ
• Function: The 3-beta-HSD enzymatic system plays a crucial role in the biosynthesis of all classes of hormonal steroids. HSD VII is active against four 7-alpha-hydroxylated sterols. Does not metabolize several different C(19/21) steroids as substrates. Involved in bile acid synthesis. Plays a key role in cell positioning and movement in lymphoid tissues by mediating degradation of 7-alpha,25-dihydroxycholesterol (7-alpha,25-OHC): 7-alpha,25-OHC acts as a ligand for the G protein-coupled receptor GPR183/EBI2, a chemotactic receptor for a number of lymphoid cells.
• KEGG Pathway:
  Primary bile acid biosynthesis (hsa00120)
  Metabolic pathways (hsa01100)
• Reactome Pathway:
  Synthesis of bile acids and bile salts via 24-hydroxycholesterol (R-HSA-193775)
  Synthesis of bile acids and bile salts via 27-hydroxycholesterol (R-HSA-193807)
  Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol (R-HSA-193368)

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cholestasis	DISDJJWE	Definitive	Biomarker	[1]
Congenital bile acid synthesis defect 1	DIS1LUZT	Definitive	Autosomal recessive	[2]
Neoplasm	DISZKGEW	Definitive	Biomarker	[3]
Progressive familial intrahepatic cholestasis type 1	DISU0AJE	Strong	Genetic Variation	[4]
Progressive familial intrahepatic cholestasis	DIS3J8HT	Limited	Genetic Variation	[4]

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 3 beta-hydroxysteroid dehydrogenase type 7 (HSD3B7).	[5]

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 3 beta-hydroxysteroid dehydrogenase type 7 (HSD3B7).	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of 3 beta-hydroxysteroid dehydrogenase type 7 (HSD3B7).	[7]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of 3 beta-hydroxysteroid dehydrogenase type 7 (HSD3B7).	[8]
Obeticholic acid	DM3Q1SM	Approved	Obeticholic acid decreases the expression of 3 beta-hydroxysteroid dehydrogenase type 7 (HSD3B7).	[9]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of 3 beta-hydroxysteroid dehydrogenase type 7 (HSD3B7).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of 3 beta-hydroxysteroid dehydrogenase type 7 (HSD3B7).	[11]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of 3 beta-hydroxysteroid dehydrogenase type 7 (HSD3B7).	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of 3 beta-hydroxysteroid dehydrogenase type 7 (HSD3B7).	[13]

References

• [1] Towards a systematic analysis of human short-chain dehydrogenases/reductases (SDR): Ligand identification and structure-activity relationships. Chem Biol Interact. 2015 Jun 5;234:114-25.
• [2] 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.
• [3] CTL recognition of a novel HLA-A*0201-binding peptide derived from glioblastoma multiforme tumor cells.Cancer Immunol Immunother. 2011 Sep;60(9):1319-32. doi: 10.1007/s00262-011-1032-4. Epub 2011 May 29.
• [4] Cryptogenic cholestasis in young and adults: ATP8B1, ABCB11, ABCB4, and TJP2 gene variants analysis by high-throughput sequencing.J Gastroenterol. 2018 Aug;53(8):945-958. doi: 10.1007/s00535-017-1423-1. Epub 2017 Dec 13.
• [5] 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.
• [6] 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.
• [7] 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.
• [8] 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.
• [9] Pharmacotoxicology of clinically-relevant concentrations of obeticholic acid in an organotypic human hepatocyte system. Toxicol In Vitro. 2017 Mar;39:93-103.
• [10] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [11] 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.
• [12] 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.
• [13] Bisphenol A and bisphenol S induce distinct transcriptional profiles in differentiating human primary preadipocytes. PLoS One. 2016 Sep 29;11(9):e0163318.