Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTQRET2B)

• DOT Name: 3-oxo-5-alpha-steroid 4-dehydrogenase 1 (SRD5A1)
• Synonyms: EC 1.3.1.22; SR type 1; Steroid 5-alpha-reductase 1; S5AR 1
• Gene Name: SRD5A1
• UniProt ID: S5A1_HUMAN
• EC Number: 1.3.1.22
• Pfam ID: PF02544
• Sequence:
  MATATGVAEERLLAALAYLQCAVGCAVFARNRQTNSVYGRHALPSHRLRVPARAAWVVQE
  LPSLALPLYQYASESAPRLRSAPNCILLAMFLVHYGHRCLIYPFLMRGGKPMPLLACTMA
  IMFCTCNGYLQSRYLSHCAVYADDWVTDPRFLIGFGLWLTGMLINIHSDHILRNLRKPGD
  TGYKIPRGGLFEYVTAANYFGEIMEWCGYALASWSVQGAAFAFFTFCFLSGRAKEHHEWY
  LRKFEEYPKFRKIIIPFLF
• Function: Converts testosterone into 5-alpha-dihydrotestosterone and progesterone or corticosterone into their corresponding 5-alpha-3-oxosteroids. It plays a central role in sexual differentiation and androgen physiology.
• Tissue Specificity: Liver and prostate (at a low level).
• KEGG Pathway:
  Steroid hormone biosynthesis (hsa00140)
  Metabolic pathways (hsa01100)
• Reactome Pathway: Androgen biosynthesis (R-HSA-193048)
• BioCyc Pathway: MetaCyc:HS07261-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Drug Response of 3 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Topotecan	DMP6G8T	Approved	3-oxo-5-alpha-steroid 4-dehydrogenase 1 (SRD5A1) affects the response to substance of Topotecan.	[17]
Mitoxantrone	DMM39BF	Approved	3-oxo-5-alpha-steroid 4-dehydrogenase 1 (SRD5A1) affects the response to substance of Mitoxantrone.	[17]
Vinblastine	DM5TVS3	Approved	3-oxo-5-alpha-steroid 4-dehydrogenase 1 (SRD5A1) affects the response to substance of Vinblastine.	[17]

This DOT Affected the Biotransformations of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
ELTANOLONE	DM38CIV	Discontinued in Phase 3	3-oxo-5-alpha-steroid 4-dehydrogenase 1 (SRD5A1) increases the chemical synthesis of ELTANOLONE.	[18]

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 3-oxo-5-alpha-steroid 4-dehydrogenase 1 (SRD5A1).	[1]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of 3-oxo-5-alpha-steroid 4-dehydrogenase 1 (SRD5A1).	[2]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of 3-oxo-5-alpha-steroid 4-dehydrogenase 1 (SRD5A1).	[3]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of 3-oxo-5-alpha-steroid 4-dehydrogenase 1 (SRD5A1).	[4]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of 3-oxo-5-alpha-steroid 4-dehydrogenase 1 (SRD5A1).	[5]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of 3-oxo-5-alpha-steroid 4-dehydrogenase 1 (SRD5A1).	[6]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of 3-oxo-5-alpha-steroid 4-dehydrogenase 1 (SRD5A1).	[7]
Dutasteride	DMQ4TJK	Approved	Dutasteride decreases the expression of 3-oxo-5-alpha-steroid 4-dehydrogenase 1 (SRD5A1).	[8]
Hydroxyflutamide	DMGIZF5	Approved	Hydroxyflutamide decreases the expression of 3-oxo-5-alpha-steroid 4-dehydrogenase 1 (SRD5A1).	[9]
Dydrogesterone	DMAKIDV	Approved	Dydrogesterone decreases the expression of 3-oxo-5-alpha-steroid 4-dehydrogenase 1 (SRD5A1).	[6]
Finasteride	DMWV3TZ	Approved	Finasteride decreases the activity of 3-oxo-5-alpha-steroid 4-dehydrogenase 1 (SRD5A1).	[10]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of 3-oxo-5-alpha-steroid 4-dehydrogenase 1 (SRD5A1).	[11]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of 3-oxo-5-alpha-steroid 4-dehydrogenase 1 (SRD5A1).	[12]
Afimoxifene	DMFORDT	Phase 2	Afimoxifene increases the expression of 3-oxo-5-alpha-steroid 4-dehydrogenase 1 (SRD5A1).	[13]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of 3-oxo-5-alpha-steroid 4-dehydrogenase 1 (SRD5A1).	[14]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of 3-oxo-5-alpha-steroid 4-dehydrogenase 1 (SRD5A1).	[15]
Tributylstannanyl	DMHN7CB	Investigative	Tributylstannanyl decreases the activity of 3-oxo-5-alpha-steroid 4-dehydrogenase 1 (SRD5A1).	[16]
1,2-dibromo-4-(1,2-dibromoethyl)cyclohexane	DMDJYHK	Investigative	1,2-dibromo-4-(1,2-dibromoethyl)cyclohexane increases the expression of 3-oxo-5-alpha-steroid 4-dehydrogenase 1 (SRD5A1).	[9]
4-MA	DMNCVIP	Investigative	4-MA decreases the activity of 3-oxo-5-alpha-steroid 4-dehydrogenase 1 (SRD5A1).	[10]

References

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• [3] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [4] Arsenic trioxide and cisplatin synergism increase cytotoxicity in human ovarian cancer cells: therapeutic potential for ovarian cancer. Cancer Sci. 2009 Dec;100(12):2459-64.
• [5] Effects of low dose treatment of tributyltin on the regulation of estrogen receptor functions in MCF-7 cells. Toxicol Appl Pharmacol. 2013 Jun 1;269(2):176-86.
• [6] Progestin effects on expression of AKR1C1-AKR1C3, SRD5A1 and PGR in the Z-12 endometriotic epithelial cell line. Chem Biol Interact. 2013 Feb 25;202(1-3):218-25.
• [7] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [8] Dutasteride affects progesterone metabolizing enzyme activity/expression in human breast cell lines resulting in suppression of cell proliferation and detachment. J Steroid Biochem Mol Biol. 2006 Aug;100(4-5):129-40.
• [9] 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.
• [10] Inhibition of the activity of 'basic' 5 alpha-reductase (type 1) detected in DU 145 cells and expressed in insect cells. J Steroid Biochem Mol Biol. 1994 Mar;48(4):347-52.
• [11] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [12] Antiandrogenic mechanisms of pesticides in human LNCaP prostate and H295R adrenocortical carcinoma cells. Toxicol Sci. 2015 Jan;143(1):126-35.
• [13] Gene expression preferentially regulated by tamoxifen in breast cancer cells and correlations with clinical outcome. Cancer Res. 2006 Jul 15;66(14):7334-40.
• [14] Highly active combination of BRD4 antagonist and histone deacetylase inhibitor against human acute myelogenous leukemia cells. Mol Cancer Ther. 2014 May;13(5):1142-54.
• [15] 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.
• [16] Effects of butyltins on human 5alpha-reductase type 1 and type 2 activity. Steroids. 2002 Sep;67(10):859-67.
• [17] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.
• [18] Important roles of the AKR1C2 and SRD5A1 enzymes in progesterone metabolism in endometrial cancer model cell lines. Chem Biol Interact. 2015 Jun 5;234:297-308. doi: 10.1016/j.cbi.2014.11.012. Epub 2014 Nov 23.