Details of Drug Off-Target (DOT)

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

• DOT Name: Steryl-sulfatase (STS)
• Synonyms: EC 3.1.6.2; Arylsulfatase C; ASC; Estrone sulfatase; Steroid sulfatase; Steryl-sulfate sulfohydrolase
• Gene Name: STS
• Related Disease: Recessive X-linked ichthyosis
• UniProt ID: STS_HUMAN
• PDB ID: 1P49; 8EG3
• EC Number: 3.1.6.2
• Pfam ID: PF00884 ; PF14707
• Sequence:
  MPLRKMKIPFLLLFFLWEAESHAASRPNIILVMADDLGIGDPGCYGNKTIRTPNIDRLAS
  GGVKLTQHLAASPLCTPSRAAFMTGRYPVRSGMASWSRTGVFLFTASSGGLPTDEITFAK
  LLKDQGYSTALIGKWHLGMSCHSKTDFCHHPLHHGFNYFYGISLTNLRDCKPGEGSVFTT
  GFKRLVFLPLQIVGVTLLTLAALNCLGLLHVPLGVFFSLLFLAALILTLFLGFLHYFRPL
  NCFMMRNYEIIQQPMSYDNLTQRLTVEAAQFIQRNTETPFLLVLSYLHVHTALFSSKDFA
  GKSQHGVYGDAVEEMDWSVGQILNLLDELRLANDTLIYFTSDQGAHVEEVSSKGEIHGGS
  NGIYKGGKANNWEGGIRVPGILRWPRVIQAGQKIDEPTSNMDIFPTVAKLAGAPLPEDRI
  IDGRDLMPLLEGKSQRSDHEFLFHYCNAYLNAVRWHPQNSTSIWKAFFFTPNFNPVGSNG
  CFATHVCFCFGSYVTHHDPPLLFDISKDPRERNPLTPASEPRFYEILKVMQEAADRHTQT
  LPEVPDQFSWNNFLWKPWLQLCCPSTGLSCQCDREKQDKRLSR
• Function: Catalyzes the conversion of sulfated steroid precursors, such as dehydroepiandrosterone sulfate (DHEA-S) and estrone sulfate to the free steroid.
• KEGG Pathway:
  Steroid hormone biosynthesis (hsa00140)
  Metabolic pathways (hsa01100)
• Reactome Pathway:
  Metabolism of steroid hormones (R-HSA-196071)
  Glycosphingolipid catabolism (R-HSA-9840310)
  The activation of arylsulfatases (R-HSA-1663150)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Recessive X-linked ichthyosis	DISZY56W	Definitive	X-linked	[1]

This DOT Affected the Biotransformations of 3 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Estrone	DM5T6US	Approved	Steryl-sulfatase (STS) increases the chemical synthesis of Estrone.	[28]
Prasterone	DM67VKL	Approved	Steryl-sulfatase (STS) increases the chemical synthesis of Prasterone.	[28]
[3H]estrone-3-sulphate	DMGPF0N	Investigative	Steryl-sulfatase (STS) decreases the sulfation of [3H]estrone-3-sulphate.	[12]

This DOT Affected the Regulation of Drug Effects of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Dehydroepiandrosterone sulfate	DM4Q80H	Approved	Steryl-sulfatase (STS) affects the metabolism of Dehydroepiandrosterone sulfate.	[28]
Equilenin	DMHO56W	Investigative	Steryl-sulfatase (STS) increases the metabolism of Equilenin.	[15]

38 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Steryl-sulfatase (STS).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Steryl-sulfatase (STS).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Steryl-sulfatase (STS).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Steryl-sulfatase (STS).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Steryl-sulfatase (STS).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Steryl-sulfatase (STS).	[7]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Steryl-sulfatase (STS).	[8]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Steryl-sulfatase (STS).	[9]
Demecolcine	DMCZQGK	Approved	Demecolcine decreases the expression of Steryl-sulfatase (STS).	[10]
Bortezomib	DMNO38U	Approved	Bortezomib decreases the expression of Steryl-sulfatase (STS).	[11]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol decreases the activity of Steryl-sulfatase (STS).	[12]
Azathioprine	DMMZSXQ	Approved	Azathioprine increases the expression of Steryl-sulfatase (STS).	[9]
Diclofenac	DMPIHLS	Approved	Diclofenac increases the expression of Steryl-sulfatase (STS).	[9]
Piroxicam	DMTK234	Approved	Piroxicam increases the expression of Steryl-sulfatase (STS).	[9]
DTI-015	DMXZRW0	Approved	DTI-015 increases the expression of Steryl-sulfatase (STS).	[13]
Alitretinoin	DMME8LH	Approved	Alitretinoin increases the activity of Steryl-sulfatase (STS).	[14]
Prednisolone	DMQ8FR2	Approved	Prednisolone increases the expression of Steryl-sulfatase (STS).	[9]
Methylprednisolone	DM4BDON	Approved	Methylprednisolone increases the expression of Steryl-sulfatase (STS).	[9]
Phosphate	DMUXQG7	Approved	Phosphate decreases the activity of Steryl-sulfatase (STS).	[15]
Danazol	DML8KTN	Approved	Danazol decreases the activity of Steryl-sulfatase (STS).	[16]
Tazarotene	DM8SMD1	Approved	Tazarotene increases the activity of Steryl-sulfatase (STS).	[14]
Curcumin	DMQPH29	Phase 3	Curcumin decreases the expression of Steryl-sulfatase (STS).	[17]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Steryl-sulfatase (STS).	[18]
Afimoxifene	DMFORDT	Phase 2	Afimoxifene decreases the expression of Steryl-sulfatase (STS).	[19]
phorbol 12-myristate 13-acetate	DMJWD62	Phase 2	phorbol 12-myristate 13-acetate increases the expression of Steryl-sulfatase (STS).	[20]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Steryl-sulfatase (STS).	[22]
IRX-5183	DMCED9U	Phase 1	IRX-5183 increases the activity of Steryl-sulfatase (STS).	[14]
PMID27336223-Compound-5	DM6E50A	Patented	PMID27336223-Compound-5 increases the activity of Steryl-sulfatase (STS).	[14]
Torcetrapib	DMDHYM7	Discontinued in Phase 2	Torcetrapib increases the expression of Steryl-sulfatase (STS).	[23]
HE2100	DMCP2KH	Discontinued in Phase 1	HE2100 decreases the activity of Steryl-sulfatase (STS).	[16]
MG-132	DMKA2YS	Preclinical	MG-132 decreases the expression of Steryl-sulfatase (STS).	[24]
ZK-119010	DMKFYDE	Terminated	ZK-119010 decreases the activity of Steryl-sulfatase (STS).	[25]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Steryl-sulfatase (STS).	[26]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Steryl-sulfatase (STS).	[10]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Steryl-sulfatase (STS).	[27]
TTNPB	DMSABD0	Investigative	TTNPB increases the activity of Steryl-sulfatase (STS).	[14]
Nitrocatechol sulfate	DMGUNIL	Investigative	Nitrocatechol sulfate decreases the activity of Steryl-sulfatase (STS).	[15]
ZK-164015	DMROWV8	Investigative	ZK-164015 decreases the activity of Steryl-sulfatase (STS).	[25]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Steryl-sulfatase (STS).	[21]

References

• [1] Cloning and expression of steroid sulfatase cDNA and the frequent occurrence of deletions in STS deficiency: implications for X-Y interchange. Cell. 1987 May 22;49(4):443-54. doi: 10.1016/0092-8674(87)90447-8.
• [2] 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.
• [3] 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.
• [4] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [5] 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.
• [6] 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.
• [7] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [8] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [9] Antirheumatic drug response signatures in human chondrocytes: potential molecular targets to stimulate cartilage regeneration. Arthritis Res Ther. 2009;11(1):R15.
• [10] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [11] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [12] Stilbene-based inhibitors of estrone sulfatase with a dual mode of action in human breast cancer cells. Arch Pharm (Weinheim). 2004 Dec;337(12):634-44. doi: 10.1002/ardp.200400904.
• [13] Gene expression profile induced by BCNU in human glioma cell lines with differential MGMT expression. J Neurooncol. 2005 Jul;73(3):189-98.
• [14] Retinoid-mediated stimulation of steroid sulfatase activity in myeloid leukemic cell lines requires RARalpha and RXR and involves the phosphoinositide 3-kinase and ERK-MAP kinase pathways. J Cell Biochem. 2006 Feb 1;97(2):327-50. doi: 10.1002/jcb.20579.
• [15] Simultaneous azo-coupling method for an estrogen sulfatase in human tissues. Histochemistry. 1983;78(2):241-9. doi: 10.1007/BF00489502.
• [16] Synthesis and steroid sulphatase inhibitory activity of C19- and C21-steroidal derivatives bearing a benzyl-inhibiting group. Eur J Med Chem. 2001 Jul-Aug;36(7-8):659-71. doi: 10.1016/s0223-5234(01)01262-4.
• [17] Gene-expression profiling during curcumin-induced apoptosis reveals downregulation of CXCR4. Exp Hematol. 2007 Jan;35(1):84-95.
• [18] Dose- and time-dependent transcriptional response of Ishikawa cells exposed to genistein. Toxicol Sci. 2016 May;151(1):71-87.
• [19] Gene expression preferentially regulated by tamoxifen in breast cancer cells and correlations with clinical outcome. Cancer Res. 2006 Jul 15;66(14):7334-40.
• [20] Hepatic steroid sulfatase critically determines estrogenic activities of conjugated equine estrogens in human cells in vitro and in mice. J Biol Chem. 2019 Aug 9;294(32):12112-12121. doi: 10.1074/jbc.RA119.009181. Epub 2019 Jun 19.
• [21] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [22] BET bromodomain inhibition targets both c-Myc and IL7R in high-risk acute lymphoblastic leukemia. Blood. 2012 Oct 4;120(14):2843-52.
• [23] Clarifying off-target effects for torcetrapib using network pharmacology and reverse docking approach. BMC Syst Biol. 2012 Dec 10;6:152.
• [24] Induction of steroid sulfatase expression in PC-3 human prostate cancer cells by insulin-like growth factor II. Toxicol Lett. 2013 Nov 25;223(2):109-15. doi: 10.1016/j.toxlet.2013.09.006. Epub 2013 Sep 18.
• [25] Sulfamoyloxy-substituted 2-phenylindoles: antiestrogen-based inhibitors of the steroid sulfatase in human breast cancer cells. Bioorg Med Chem. 2002 Dec;10(12):3941-53. doi: 10.1016/s0968-0896(02)00306-1.
• [26] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [27] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [28] Steroid signalling in the ovarian surface epithelium. Trends Endocrinol Metab. 2005 Sep;16(7):327-33.