Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTSK1DTP)

• DOT Name: Short-chain dehydrogenase/reductase 3 (DHRS3)
• Synonyms: EC 1.1.1.300; DD83.1; Retinal short-chain dehydrogenase/reductase 1; retSDR1; Retinol dehydrogenase 17; Short chain dehydrogenase/reductase family 16C member 1
• Gene Name: DHRS3
• UniProt ID: DHRS3_HUMAN
• EC Number: 1.1.1.300
• Pfam ID: PF00106
• Sequence:
  MVWKRLGALVMFPLQMIYLVVKAAVGLVLPAKLRDLSRENVLITGGGRGIGRQLAREFAE
  RGARKIVLWGRTEKCLKETTEEIRQMGTECHYFICDVGNREEVYQTAKAVREKVGDITIL
  VNNAAVVHGKSLMDSDDDALLKSQHINTLGQFWTTKAFLPRMLELQNGHIVCLNSVLALS
  AIPGAIDYCTSKASAFAFMESLTLGLLDCPGVSATTVLPFHTSTEMFQGMRVRFPNLFPP
  LKPETVARRTVEAVQLNQALLLLPWTMHALVILKSILPQAALEEIHKFSGTYTCMNTFKG
  RT
• Function: Catalyzes the reduction of all-trans-retinal to all-trans-retinol in the presence of NADPH.
• Tissue Specificity: Widely expressed with highest levels found in heart, placenta, lung, liver, kidney, pancreas, thyroid, testis, stomach, trachea and spinal cord. Lower levels found in skeletal muscle, intestine and lymph node. No expression detected in brain. In the retina, expressed in cone but not rod outer segments.
• KEGG Pathway:
  Retinol metabolism (hsa00830)
  Metabolic pathways (hsa01100)
  Biosynthesis of cofactors (hsa01240)
• Reactome Pathway:
  RA biosynthesis pathway (R-HSA-5365859)
  The retinoid cycle in cones (daylight vision) (R-HSA-2187335)
• BioCyc Pathway: MetaCyc:ENSG00000162496-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
DTI-015	DMXZRW0	Approved	Short-chain dehydrogenase/reductase 3 (DHRS3) affects the response to substance of DTI-015.	[33]

This DOT Affected the Regulation of Drug Effects of 5 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Estrone	DM5T6US	Approved	Short-chain dehydrogenase/reductase 3 (DHRS3) increases the metabolism of Estrone.	[34]
BRN-3548355	DM4KXT0	Investigative	Short-chain dehydrogenase/reductase 3 (DHRS3) increases the metabolism of BRN-3548355.	[34]
4-ANDROSTENE-3-17-DIONE	DMSE8NU	Investigative	Short-chain dehydrogenase/reductase 3 (DHRS3) increases the metabolism of 4-ANDROSTENE-3-17-DIONE.	[34]
2,3-dihydroxypropanal	DMOWNB4	Investigative	Short-chain dehydrogenase/reductase 3 (DHRS3) increases the metabolism of 2,3-dihydroxypropanal.	[34]
BENZIL	DM5Y2M8	Investigative	Short-chain dehydrogenase/reductase 3 (DHRS3) increases the metabolism of BENZIL.	[34]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Short-chain dehydrogenase/reductase 3 (DHRS3).	[1]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Short-chain dehydrogenase/reductase 3 (DHRS3).	[31]

35 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 Short-chain dehydrogenase/reductase 3 (DHRS3).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Short-chain dehydrogenase/reductase 3 (DHRS3).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Short-chain dehydrogenase/reductase 3 (DHRS3).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Short-chain dehydrogenase/reductase 3 (DHRS3).	[5]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Short-chain dehydrogenase/reductase 3 (DHRS3).	[6]
Arsenic	DMTL2Y1	Approved	Arsenic affects the expression of Short-chain dehydrogenase/reductase 3 (DHRS3).	[7]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Short-chain dehydrogenase/reductase 3 (DHRS3).	[8]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Short-chain dehydrogenase/reductase 3 (DHRS3).	[9]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Short-chain dehydrogenase/reductase 3 (DHRS3).	[10]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Short-chain dehydrogenase/reductase 3 (DHRS3).	[11]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of Short-chain dehydrogenase/reductase 3 (DHRS3).	[12]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Short-chain dehydrogenase/reductase 3 (DHRS3).	[13]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Short-chain dehydrogenase/reductase 3 (DHRS3).	[14]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of Short-chain dehydrogenase/reductase 3 (DHRS3).	[15]
Isotretinoin	DM4QTBN	Approved	Isotretinoin increases the expression of Short-chain dehydrogenase/reductase 3 (DHRS3).	[16]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol increases the expression of Short-chain dehydrogenase/reductase 3 (DHRS3).	[17]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone increases the expression of Short-chain dehydrogenase/reductase 3 (DHRS3).	[18]
Nicotine	DMWX5CO	Approved	Nicotine increases the expression of Short-chain dehydrogenase/reductase 3 (DHRS3).	[19]
Dasatinib	DMJV2EK	Approved	Dasatinib increases the expression of Short-chain dehydrogenase/reductase 3 (DHRS3).	[20]
Ethinyl estradiol	DMODJ40	Approved	Ethinyl estradiol increases the expression of Short-chain dehydrogenase/reductase 3 (DHRS3).	[21]
Bexarotene	DMOBIKY	Approved	Bexarotene increases the expression of Short-chain dehydrogenase/reductase 3 (DHRS3).	[22]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Short-chain dehydrogenase/reductase 3 (DHRS3).	[23]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Short-chain dehydrogenase/reductase 3 (DHRS3).	[14]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of Short-chain dehydrogenase/reductase 3 (DHRS3).	[17]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene increases the expression of Short-chain dehydrogenase/reductase 3 (DHRS3).	[3]
Fenretinide	DMRD5SP	Phase 3	Fenretinide increases the expression of Short-chain dehydrogenase/reductase 3 (DHRS3).	[24]
Rigosertib	DMOSTXF	Phase 3	Rigosertib affects the expression of Short-chain dehydrogenase/reductase 3 (DHRS3).	[25]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Short-chain dehydrogenase/reductase 3 (DHRS3).	[17]
GSK2110183	DMZHB37	Phase 2	GSK2110183 increases the expression of Short-chain dehydrogenase/reductase 3 (DHRS3).	[26]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Short-chain dehydrogenase/reductase 3 (DHRS3).	[27]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Short-chain dehydrogenase/reductase 3 (DHRS3).	[28]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Short-chain dehydrogenase/reductase 3 (DHRS3).	[29]
PMID27336223-Compound-5	DM6E50A	Patented	PMID27336223-Compound-5 increases the expression of Short-chain dehydrogenase/reductase 3 (DHRS3).	[18]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of Short-chain dehydrogenase/reductase 3 (DHRS3).	[30]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Short-chain dehydrogenase/reductase 3 (DHRS3).	[32]

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] 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] Differential modulation of PI3-kinase/Akt pathway during all-trans retinoic acid- and Am80-induced HL-60 cell differentiation revealed by DNA microarray analysis. Biochem Pharmacol. 2004 Dec 1;68(11):2177-86.
• [4] 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.
• [5] RNA sequence analysis of inducible pluripotent stem cell-derived cardiomyocytes reveals altered expression of DNA damage and cell cycle genes in response to doxorubicin. Toxicol Appl Pharmacol. 2018 Oct 1;356:44-53.
• [6] Long-term estrogen exposure promotes carcinogen bioactivation, induces persistent changes in gene expression, and enhances the tumorigenicity of MCF-7 human breast cancer cells. Toxicol Appl Pharmacol. 2009 Nov 1;240(3):355-66.
• [7] Drinking-water arsenic exposure modulates gene expression in human lymphocytes from a U.S. population. Environ Health Perspect. 2008 Apr;116(4):524-31. doi: 10.1289/ehp.10861.
• [8] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [9] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [10] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [11] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [12] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [13] Endometrial receptivity is affected in women with high circulating progesterone levels at the end of the follicular phase: a functional genomics analysis. Hum Reprod. 2011 Jul;26(7):1813-25.
• [14] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [15] 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.
• [16] Gene microarray analysis of human renal cell carcinoma: the effects of HDAC inhibition and retinoid treatment. Cancer Biol Ther. 2008 Oct;7(10):1607-18.
• [17] Gene expression profiling in Ishikawa cells: a fingerprint for estrogen active compounds. Toxicol Appl Pharmacol. 2009 Apr 1;236(1):85-96.
• [18] PPARgamma controls CD1d expression by turning on retinoic acid synthesis in developing human dendritic cells. J Exp Med. 2006 Oct 2;203(10):2351-62.
• [19] Characterizing the genetic basis for nicotine induced cancer development: a transcriptome sequencing study. PLoS One. 2013 Jun 18;8(6):e67252.
• [20] Dasatinib reverses cancer-associated fibroblasts (CAFs) from primary lung carcinomas to a phenotype comparable to that of normal fibroblasts. Mol Cancer. 2010 Jun 27;9:168.
• [21] The genomic response of a human uterine endometrial adenocarcinoma cell line to 17alpha-ethynyl estradiol. Toxicol Sci. 2009 Jan;107(1):40-55.
• [22] Identification of biomarkers modulated by the rexinoid LGD1069 (bexarotene) in human breast cells using oligonucleotide arrays. Cancer Res. 2006 Dec 15;66(24):12009-18.
• [23] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [24] The transforming growth factor-beta family members bone morphogenetic protein-2 and macrophage inhibitory cytokine-1 as mediators of the antiangiogenic activity of N-(4-hydroxyphenyl)retinamide. Clin Cancer Res. 2005 Jun 15;11(12):4610-9.
• [25] ON 01910.Na is selectively cytotoxic for chronic lymphocytic leukemia cells through a dual mechanism of action involving PI3K/AKT inhibition and induction of oxidative stress. Clin Cancer Res. 2012 Apr 1;18(7):1979-91. doi: 10.1158/1078-0432.CCR-11-2113. Epub 2012 Feb 20.
• [26] Novel ATP-competitive Akt inhibitor afuresertib suppresses the proliferation of malignant pleural mesothelioma cells. Cancer Med. 2017 Nov;6(11):2646-2659. doi: 10.1002/cam4.1179. Epub 2017 Sep 27.
• [27] 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.
• [28] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [29] 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.
• [30] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [31] Expression and DNA methylation changes in human breast epithelial cells after bisphenol A exposure. Int J Oncol. 2012 Jul;41(1):369-77.
• [32] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [33] Tumor necrosis factor-alpha-induced protein 3 as a putative regulator of nuclear factor-kappaB-mediated resistance to O6-alkylating agents in human glioblastomas. J Clin Oncol. 2006 Jan 10;24(2):274-87. doi: 10.1200/JCO.2005.02.9405. Epub 2005 Dec 19.
• [34] Molecular and biochemical characterisation of human short-chain dehydrogenase/reductase member 3 (DHRS3). Chem Biol Interact. 2015 Jun 5;234:178-87.