Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTGPJ517)

• DOT Name: Sulfotransferase 1E1 (SULT1E1)
• Synonyms: ST1E1; EC 2.8.2.4; EST-1; Estrogen sulfotransferase; Sulfotransferase, estrogen-preferring
• Gene Name: SULT1E1
• UniProt ID: ST1E1_HUMAN
• PDB ID: 1G3M; 1HY3; 4JVL; 4JVM; 4JVN
• EC Number: 2.8.2.4
• Pfam ID: PF00685
• Sequence:
  MNSELDYYEKFEEVHGILMYKDFVKYWDNVEAFQARPDDLVIATYPKSGTTWVSEIVYMI
  YKEGDVEKCKEDVIFNRIPFLECRKENLMNGVKQLDEMNSPRIVKTHLPPELLPASFWEK
  DCKIIYLCRNAKDVAVSFYYFFLMVAGHPNPGSFPEFVEKFMQGQVPYGSWYKHVKSWWE
  KGKSPRVLFLFYEDLKEDIRKEVIKLIHFLERKPSEELVDRIIHHTSFQEMKNNPSTNYT
  TLPDEIMNQKLSPFMRKGITGDWKNHFTVALNEKFDKHYEQQMKESTLKFRTEI
• Function: Sulfotransferase that utilizes 3'-phospho-5'-adenylyl sulfate (PAPS) as sulfonate donor to catalyze the sulfate conjugation of estradiol and estrone. Is a key enzyme in estrogen homeostasis, the sulfation of estrogens leads to their inactivation. Also sulfates dehydroepiandrosterone (DHEA), pregnenolone, (24S)-hydroxycholesterol and xenobiotic compounds like ethinylestradiol, equalenin, diethyl stilbesterol and 1-naphthol at significantly lower efficiency. Does not sulfonate cortisol, testosterone and dopamine. May play a role in gut microbiota-host metabolic interaction. O-sulfonates 4-ethylphenol (4-EP), a dietary tyrosine-derived metabolite produced by gut bacteria. The product 4-EPS crosses the blood-brain barrier and may negatively regulate oligodendrocyte maturation and myelination, affecting the functional connectivity of different brain regions associated with the limbic system.
• Tissue Specificity: Liver, intestine and at lower level in the kidney.
• KEGG Pathway:
  Steroid hormone biosynthesis (hsa00140)
  Metabolic pathways (hsa01100)
• Reactome Pathway:
  Paracetamol ADME (R-HSA-9753281)
  Cytosolic sulfonation of small molecules (R-HSA-156584)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Biotransformations of 4 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Triclosan	DMZUR4N	Approved	Sulfotransferase 1E1 (SULT1E1) increases the sulfation of Triclosan.	[22]
Prasterone	DM67VKL	Approved	Sulfotransferase 1E1 (SULT1E1) increases the sulfation of Prasterone.	[23]
Ropivacaine	DMSPJG2	Approved	Sulfotransferase 1E1 (SULT1E1) increases the sulfation of Ropivacaine.	[24]
Mononitrophenol	DM4QO9G	Investigative	Sulfotransferase 1E1 (SULT1E1) increases the sulfation of Mononitrophenol.	[23]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Hydroxymethylpyrene	DMPGAR2	Investigative	Sulfotransferase 1E1 (SULT1E1) increases the activity of Hydroxymethylpyrene.	[25]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Sulfotransferase 1E1 (SULT1E1).	[1]
Estradiol	DMUNTE3	Approved	Estradiol decreases the activity of Sulfotransferase 1E1 (SULT1E1).	[2]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Sulfotransferase 1E1 (SULT1E1).	[3]
Phenobarbital	DMXZOCG	Approved	Phenobarbital decreases the expression of Sulfotransferase 1E1 (SULT1E1).	[4]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Sulfotransferase 1E1 (SULT1E1).	[5]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Sulfotransferase 1E1 (SULT1E1).	[6]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol decreases the activity of Sulfotransferase 1E1 (SULT1E1).	[2]
Ethanol	DMDRQZU	Approved	Ethanol decreases the activity of Sulfotransferase 1E1 (SULT1E1).	[7]
Sodium lauryl sulfate	DMLJ634	Approved	Sodium lauryl sulfate decreases the expression of Sulfotransferase 1E1 (SULT1E1).	[8]
Ethinyl estradiol	DMODJ40	Approved	Ethinyl estradiol decreases the activity of Sulfotransferase 1E1 (SULT1E1).	[2]
Sulindac	DM2QHZU	Approved	Sulindac decreases the activity of Sulfotransferase 1E1 (SULT1E1).	[9]
Ibuprofen	DM8VCBE	Approved	Ibuprofen decreases the activity of Sulfotransferase 1E1 (SULT1E1).	[9]
Estrone	DM5T6US	Approved	Estrone decreases the activity of Sulfotransferase 1E1 (SULT1E1).	[2]
Chenodiol	DMQ8JIK	Approved	Chenodiol decreases the expression of Sulfotransferase 1E1 (SULT1E1).	[10]
Bosentan	DMIOGBU	Approved	Bosentan affects the expression of Sulfotransferase 1E1 (SULT1E1).	[11]
Estriol	DMOEM2I	Approved	Estriol decreases the activity of Sulfotransferase 1E1 (SULT1E1).	[2]
Meclofenamic acid	DM05FXR	Approved	Meclofenamic acid decreases the activity of Sulfotransferase 1E1 (SULT1E1).	[9]
Dienestrol	DMBSXI0	Approved	Dienestrol decreases the activity of Sulfotransferase 1E1 (SULT1E1).	[2]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Sulfotransferase 1E1 (SULT1E1).	[12]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of Sulfotransferase 1E1 (SULT1E1).	[13]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Sulfotransferase 1E1 (SULT1E1).	[14]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Sulfotransferase 1E1 (SULT1E1).	[15]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Sulfotransferase 1E1 (SULT1E1).	[16]
HEXESTROL	DM9AGWQ	Withdrawn from market	HEXESTROL decreases the activity of Sulfotransferase 1E1 (SULT1E1).	[2]
Forskolin	DM6ITNG	Investigative	Forskolin decreases the expression of Sulfotransferase 1E1 (SULT1E1).	[18]
Piceatannol	DMYOP45	Investigative	Piceatannol increases the expression of Sulfotransferase 1E1 (SULT1E1).	[19]
Aloe-emodin	DMPTY8S	Investigative	Aloe-emodin decreases the activity of Sulfotransferase 1E1 (SULT1E1).	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Sulfotransferase 1E1 (SULT1E1).	[17]
2-hydroxy-17beta-estradiol	DMM9Z0B	Investigative	2-hydroxy-17beta-estradiol affects the sulfation of Sulfotransferase 1E1 (SULT1E1).	[21]

References

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• [3] Methotrexate induction of human sulfotransferases in Hep G2 and Caco-2 cells. J Appl Toxicol. 2005 Sep-Oct;25(5):354-60.
• [4] Dose- and time-dependent effects of phenobarbital on gene expression profiling in human hepatoma HepaRG cells. Toxicol Appl Pharmacol. 2009 Feb 1;234(3):345-60.
• [5] Potential hazards to embryo implantation: A human endometrial in vitro model to identify unwanted antigestagenic actions of chemicals. Toxicol Appl Pharmacol. 2012 May 1;260(3):232-40.
• [6] Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
• [7] Solvent effect on cDNA-expressed human sulfotransferase (SULT) activities in vitro. Drug Metab Dispos. 2003 Nov;31(11):1300-5.
• [8] CXCL14 downregulation in human keratinocytes is a potential biomarker for a novel in vitro skin sensitization test. Toxicol Appl Pharmacol. 2020 Jan 1;386:114828. doi: 10.1016/j.taap.2019.114828. Epub 2019 Nov 14.
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• [10] Chenodeoxycholic acid significantly impacts the expression of miRNAs and genes involved in lipid, bile acid and drug metabolism in human hepatocytes. Life Sci. 2016 Jul 1;156:47-56.
• [11] Omics-based responses induced by bosentan in human hepatoma HepaRG cell cultures. Arch Toxicol. 2018 Jun;92(6):1939-1952.
• [12] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [13] Resveratrol in human hepatoma HepG2 cells: metabolism and inducibility of detoxifying enzymes. Drug Metab Dispos. 2007 May;35(5):699-703.
• [14] Effects of endocrine disruptors on genes associated with 17beta-estradiol metabolism and excretion. Steroids. 2008 Nov;73(12):1242-51.
• [15] 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.
• [16] 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.
• [17] Expression and DNA methylation changes in human breast epithelial cells after bisphenol A exposure. Int J Oncol. 2012 Jul;41(1):369-77.
• [18] Endocrine disruption potentials of organophosphate flame retardants and related mechanisms in H295R and MVLN cell lines and in zebrafish. Aquat Toxicol. 2012 Jun 15;114-115:173-81.
• [19] Inhibition of CYP17A1 activity by resveratrol, piceatannol, and synthetic resveratrol analogs. Prostate. 2014 Jun;74(8):839-51.
• [20] The natural anthraquinones from Rheum palmatum induced the metabolic disorder of melatonin by inhibiting human CYP and SULT enzymes. Toxicol Lett. 2016 Nov 16;262:27-38.
• [21] High metabolization of catecholestrogens by type 1 estrogen sulfotransferase (hEST1). J Steroid Biochem Mol Biol. 2001 Apr;77(1):83-6. doi: 10.1016/s0960-0760(01)00025-5.
• [22] Phase II metabolism of betulin by rat and human UDP-glucuronosyltransferases and sulfotransferases. Chem Biol Interact. 2019 Apr 1;302:190-195. doi: 10.1016/j.cbi.2019.02.009. Epub 2019 Feb 15.
• [23] Human liver estrogen sulfotransferase: identification by cDNA cloning and expression. Biochem Biophys Res Commun. 1994 May 16;200(3):1621-9. doi: 10.1006/bbrc.1994.1637.
• [24] Studies on sulfation of synthesized metabolites from the local anesthetics ropivacaine and lidocaine using human cloned sulfotransferases. Drug Metab Dispos. 1999 Sep;27(9):1057-63.
• [25] Determination of sulfotransferase forms involved in the metabolic activation of the genotoxicant 1-hydroxymethylpyrene using bacterially expressed enzymes and genetically modified mouse models. Chem Res Toxicol. 2014 Jun 16;27(6):1060-9. doi: 10.1021/tx500129g. Epub 2014 May 22.