Details of Drug Off-Target (DOT)

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

• DOT Name: Dehydrogenase/reductase SDR family member 4 (DHRS4)
• Synonyms: EC 1.1.1.184; NADPH-dependent carbonyl reductase; CR; NADPH-dependent retinol dehydrogenase/reductase; NRDR; humNRDR; Peroxisomal short-chain alcohol dehydrogenase; PSCD; SCAD-SRL; Short chain dehydrogenase/reductase family 25C member 2; Protein SDR25C2; Short-chain dehydrogenase/reductase family member 4
• Gene Name: DHRS4
• Related Disease:
  Squamous cell carcinoma
  Clear cell renal carcinoma
  Neoplasm
• UniProt ID: DHRS4_HUMAN
• PDB ID: 3O4R
• EC Number: 1.1.1.184
• Pfam ID: PF13561
• Sequence:
  MHKAGLLGLCARAWNSVRMASSGMTRRDPLANKVALVTASTDGIGFAIARRLAQDGAHVV
  VSSRKQQNVDQAVATLQGEGLSVTGTVCHVGKAEDRERLVATAVKLHGGIDILVSNAAVN
  PFFGSIMDVTEEVWDKTLDINVKAPALMTKAVVPEMEKRGGGSVVIVSSIAAFSPSPGFS
  PYNVSKTALLGLTKTLAIELAPRNIRVNCLAPGLIKTSFSRMLWMDKEKEESMKETLRIR
  RLGEPEDCAGIVSFLCSEDASYITGETVVVGGGTPSRL
• Function: NADPH-dependent oxidoreductase which catalyzes the reduction of a variety of compounds bearing carbonyl groups including ketosteroids, alpha-dicarbonyl compounds, aldehydes, aromatic ketones and quinones. Reduces 3-ketosteroids and benzil into 3beta-hydroxysteroids and R-benzoin, respectively, in contrast to the stereoselectivity of non-primate DHRS4s which produce 3alpha-hydroxysteroids and S-benzoin. Diplays low activity toward all-trans-retinal and no activity toward 9-cis-retinal as compared to non-primate mammals. In the reverse reaction, catalyze the NAD-dependent oxidation of 3beta-hydroxysteroids and alcohol, but with much lower efficiency. Involved in the metabolism of 3beta-hydroxysteroids, isatin and xenobiotic carbonyl compounds ; [Isoform 7]: No detected catalytic activity in vitro, possibly due to the lack of catalytic site; [Isoform 8]: NADPH-dependent oxidoreductase which catalyzes the reduction of a variety of compounds bearing carbonyl groups including ketosteroids, alpha-dicarbonyl compounds, aldehydes, aromatic ketones and quinones. Involved in the metabolism of 3beta-hydroxysteroids, isatin and xenobiotic carbonyl compounds. Has a higher catalytic activity for xenobiotic alpha-dicarbonyl compounds, sucha as benzil, than isoform 1 and is involved in benzil detoxification.
• Tissue Specificity: .Predominantly expressed in normal cervix (at protein level).; [Isoform 4]: Expressed in some neoplastic cervical tissues, but not in normal cervix (at protein level).; [Isoform 5]: Expressed in a few neoplastic cervical tissues.; [Isoform 6]: Expressed in a few neoplastic cervical tissues.; [Isoform 8]: High expression in liver.
• KEGG Pathway:
  Retinol metabolism (hsa00830)
  Metabolic pathways (hsa01100)
  Peroxisome (hsa04146)
• Reactome Pathway:
  Peroxisomal protein import (R-HSA-9033241)
  RA biosynthesis pathway (R-HSA-5365859)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Squamous cell carcinoma	DISQVIFL	Strong	Genetic Variation	[1]
Clear cell renal carcinoma	DISBXRFJ	moderate	Biomarker	[2]
Neoplasm	DISZKGEW	moderate	Biomarker	[2]

9 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 Dehydrogenase/reductase SDR family member 4 (DHRS4).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Dehydrogenase/reductase SDR family member 4 (DHRS4).	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Dehydrogenase/reductase SDR family member 4 (DHRS4).	[5]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Dehydrogenase/reductase SDR family member 4 (DHRS4).	[7]
Selenium	DM25CGV	Approved	Selenium increases the expression of Dehydrogenase/reductase SDR family member 4 (DHRS4).	[8]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of Dehydrogenase/reductase SDR family member 4 (DHRS4).	[9]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Dehydrogenase/reductase SDR family member 4 (DHRS4).	[8]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Dehydrogenase/reductase SDR family member 4 (DHRS4).	[10]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Dehydrogenase/reductase SDR family member 4 (DHRS4).	[11]

1 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Dehydrogenase/reductase SDR family member 4 (DHRS4).	[6]

References

• [1] Expression of a novel alternatively spliced variant of NADP(H)-dependent retinol dehydrogenase/reductase with deletion of exon 3 in cervical squamous carcinoma.Int J Cancer. 2007 Apr 15;120(8):1618-26. doi: 10.1002/ijc.22306.
• [2] The downregulated long noncoding RNA DHRS4-AS1 is protumoral and associated with the prognosis of clear cell renal cell carcinoma.Onco Targets Ther. 2018 Sep 10;11:5631-5646. doi: 10.2147/OTT.S164984. eCollection 2018.
• [3] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [4] 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.
• [5] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [6] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [7] Minimal peroxide exposure of neuronal cells induces multifaceted adaptive responses. PLoS One. 2010 Dec 17;5(12):e14352. doi: 10.1371/journal.pone.0014352.
• [8] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [9] Transcriptional profiling of testosterone-regulated genes in the skeletal muscle of human immunodeficiency virus-infected men experiencing weight loss. J Clin Endocrinol Metab. 2007 Jul;92(7):2793-802. doi: 10.1210/jc.2006-2722. Epub 2007 Apr 17.
• [10] 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.
• [11] Alternatives for the worse: Molecular insights into adverse effects of bisphenol a and substitutes during human adipocyte differentiation. Environ Int. 2021 Nov;156:106730. doi: 10.1016/j.envint.2021.106730. Epub 2021 Jun 27.