Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTHJ8WWV)

• DOT Name: Sulfotransferase 1A3 (SULT1A4)
• Synonyms: ST1A3; EC 2.8.2.1; Aryl sulfotransferase 1A3/1A4; Catecholamine-sulfating phenol sulfotransferase; HAST3; M-PST; Monoamine-sulfating phenol sulfotransferase; Placental estrogen sulfotransferase; Sulfotransferase 1A3/1A4; Sulfotransferase, monoamine-preferring; Thermolabile phenol sulfotransferase; TL-PST
• Gene Name: SULT1A4
• Related Disease:
  Bacillary dysentery
  Bardet biedl syndrome
  Carpal tunnel syndrome
  CLN2 Batten disease
  Myopathy
  Neuromyelitis optica
  High blood pressure
• UniProt ID: ST1A3_HUMAN
• PDB ID: 1CJM; 2A3R
• EC Number: 2.8.2.1
• Pfam ID: PF00685
• Sequence:
  MELIQDTSRPPLEYVKGVPLIKYFAEALGPLQSFQARPDDLLINTYPKSGTTWVSQILDM
  IYQGGDLEKCNRAPIYVRVPFLEVNDPGEPSGLETLKDTPPPRLIKSHLPLALLPQTLLD
  QKVKVVYVARNPKDVAVSYYHFHRMEKAHPEPGTWDSFLEKFMAGEVSYGSWYQHVQEWW
  ELSRTHPVLYLFYEDMKENPKREIQKILEFVGRSLPEETMDFMVQHTSFKEMKKNPMTNY
  TTVPQELMDHSISPFMRKGMAGDWKTTFTVAQNERFDADYAEKMAGCSLSFRSEL
• Function: Sulfotransferase that utilizes 3'-phospho-5'-adenylyl sulfate (PAPS) as sulfonate donor to catalyze the sulfate conjugation of phenolic monoamines (neurotransmitters such as dopamine, norepinephrine and serotonin) and phenolic and catechol drugs.
• Tissue Specificity: Liver, colon, kidney, lung, brain, spleen, small intestine, placenta and leukocyte.
• KEGG Pathway: Chemical carcinogenesis - D. adducts (hsa05204)
• Reactome Pathway:
  XBP1(S) activates chaperone genes (R-HSA-381038)
  Paracetamol ADME (R-HSA-9753281)
  Cytosolic sulfonation of small molecules (R-HSA-156584)
• BioCyc Pathway: MetaCyc:HS05608-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Bacillary dysentery	DISFZHKN	Strong	Genetic Variation	[1]
Bardet biedl syndrome	DISTBNZW	Strong	Genetic Variation	[2]
Carpal tunnel syndrome	DISHQ3BE	Strong	Genetic Variation	[3]
CLN2 Batten disease	DISZC5YB	Strong	Biomarker	[4]
Myopathy	DISOWG27	Strong	Genetic Variation	[2]
Neuromyelitis optica	DISBFGKL	Strong	Biomarker	[5]
High blood pressure	DISY2OHH	Limited	Biomarker	[6]

This DOT Affected the Biotransformations of 20 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Estradiol	DMUNTE3	Approved	Sulfotransferase 1A3 (SULT1A4) increases the sulfation of Estradiol.	[18]
Triclosan	DMZUR4N	Approved	Sulfotransferase 1A3 (SULT1A4) increases the sulfation of Triclosan.	[19]
Troglitazone	DM3VFPD	Approved	Sulfotransferase 1A3 (SULT1A4) increases the sulfation of Troglitazone.	[18]
Ethinyl estradiol	DMODJ40	Approved	Sulfotransferase 1A3 (SULT1A4) increases the sulfation of Ethinyl estradiol.	[21]
Epinephrine	DM3KJBC	Approved	Sulfotransferase 1A3 (SULT1A4) increases the sulfation of Epinephrine.	[18]
Norepinephrine	DMOUC09	Approved	Sulfotransferase 1A3 (SULT1A4) increases the sulfation of Norepinephrine.	[18]
Ropivacaine	DMSPJG2	Approved	Sulfotransferase 1A3 (SULT1A4) increases the sulfation of Ropivacaine.	[22]
Phentolamine	DMXYJOB	Approved	Sulfotransferase 1A3 (SULT1A4) increases the sulfation of Phentolamine.	[18]
Benzyl alcohol	DMBVYDI	Approved	Sulfotransferase 1A3 (SULT1A4) increases the sulfation of Benzyl alcohol.	[23]
Minoxidil	DMA2Z4F	Approved	Sulfotransferase 1A3 (SULT1A4) increases the sulfation of Minoxidil.	[18]
3,4-Dihydroxycinnamic Acid	DMVZL26	Phase 4	Sulfotransferase 1A3 (SULT1A4) increases the sulfation of 3,4-Dihydroxycinnamic Acid.	[24]
Resveratrol	DM3RWXL	Phase 3	Sulfotransferase 1A3 (SULT1A4) increases the sulfation of Resveratrol.	[25]
PINOCEMBRIN	DM96VWD	Phase 2	Sulfotransferase 1A3 (SULT1A4) increases the sulfation of PINOCEMBRIN.	[18]
Clioquinol	DM746BZ	Withdrawn from market	Sulfotransferase 1A3 (SULT1A4) increases the sulfation of Clioquinol.	[26]
Serotonin	DMOFCRY	Investigative	Sulfotransferase 1A3 (SULT1A4) increases the sulfation of Serotonin.	[18]
Catechol	DML0YEK	Investigative	Sulfotransferase 1A3 (SULT1A4) increases the sulfation of Catechol.	[24]
Tyramine	DM4UXT1	Investigative	Sulfotransferase 1A3 (SULT1A4) increases the sulfation of Tyramine.	[18]
5-hydroxyindole	DMI0GMB	Investigative	Sulfotransferase 1A3 (SULT1A4) increases the sulfation of 5-hydroxyindole.	[18]
Hydroxytryptophol	DMZN3GP	Investigative	Sulfotransferase 1A3 (SULT1A4) increases the sulfation of Hydroxytryptophol.	[18]
6-hydroxymelatonin	DM89YV7	Investigative	Sulfotransferase 1A3 (SULT1A4) increases the sulfation of 6-hydroxymelatonin.	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Diethylstilbestrol	DMN3UXQ	Approved	Sulfotransferase 1A3 (SULT1A4) increases the metabolism of Diethylstilbestrol.	[20]
Estrone	DM5T6US	Approved	Sulfotransferase 1A3 (SULT1A4) increases the metabolism of Estrone.	[20]
Dopamine	DMPGUCF	Approved	Sulfotransferase 1A3 (SULT1A4) increases the metabolism of Dopamine.	[20]
N-nonylphenol	DMH3OUX	Investigative	Sulfotransferase 1A3 (SULT1A4) increases the metabolism of N-nonylphenol.	[20]
Mononitrophenol	DM4QO9G	Investigative	Sulfotransferase 1A3 (SULT1A4) increases the metabolism of Mononitrophenol.	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
2-AMINO-1-METHYL-6-PHENYLIMIDAZO[4,5-B]PYRIDINE	DMNQL17	Investigative	Sulfotransferase 1A3 (SULT1A4) increases the response to substance of 2-AMINO-1-METHYL-6-PHENYLIMIDAZO[4,5-B]PYRIDINE.	[27]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Sulfotransferase 1A3 (SULT1A4).	[7]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Sulfotransferase 1A3 (SULT1A4).	[15]
2-hydroxy-17beta-estradiol	DMM9Z0B	Investigative	2-hydroxy-17beta-estradiol affects the sulfation of Sulfotransferase 1A3 (SULT1A4).	[17]

8 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 Sulfotransferase 1A3 (SULT1A4).	[8]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Sulfotransferase 1A3 (SULT1A4).	[9]
Ethanol	DMDRQZU	Approved	Ethanol decreases the activity of Sulfotransferase 1A3 (SULT1A4).	[10]
Irinotecan	DMP6SC2	Approved	Irinotecan increases the expression of Sulfotransferase 1A3 (SULT1A4).	[11]
Vitamin C	DMXJ7O8	Approved	Vitamin C decreases the expression of Sulfotransferase 1A3 (SULT1A4).	[12]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of Sulfotransferase 1A3 (SULT1A4).	[13]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Sulfotransferase 1A3 (SULT1A4).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Sulfotransferase 1A3 (SULT1A4).	[16]

References

• [1] Epithelial Cell Damage Activates Bactericidal/Permeability Increasing-Protein (BPI) Expression in Intestinal Epithelium.Front Microbiol. 2017 Aug 15;8:1567. doi: 10.3389/fmicb.2017.01567. eCollection 2017.
• [2] Altered myogenesis and premature senescence underlie human TRIM32-related myopathy.Acta Neuropathol Commun. 2019 Mar 1;7(1):30. doi: 10.1186/s40478-019-0683-9.
• [3] The Impact of Pre-Referral Advanced Diagnostic Testing on Wait Time to See a Hand Surgeon for Common Upper-Extremity Conditions.J Hand Surg Am. 2019 Dec;44(12):1013-1020.e2. doi: 10.1016/j.jhsa.2019.09.009. Epub 2019 Oct 31.
• [4] Analysis of Batten disease candidate genes STP and STM.Am J Med Genet. 1995 Jun 5;57(2):324-6. doi: 10.1002/ajmg.1320570244.
• [5] Short segment myelitis as a first manifestation of neuromyelitis optica spectrum disorders.Mult Scler. 2017 Mar;23(3):413-419. doi: 10.1177/1352458516687043. Epub 2017 Jan 9.
• [6] Tongsaimai reverses the hypertension and left ventricular remolding caused by abdominal aortic constriction in rats.J Ethnopharmacol. 2020 Jan 10;246:112154. doi: 10.1016/j.jep.2019.112154. Epub 2019 Aug 12.
• [7] 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.
• [8] Effect of all-trans retinoic acid on sodium/iodide symporter expression, radioiodine uptake and gene expression profiles in a human anaplastic thyroid carcinoma cell line. Nucl Med Biol. 2006 Oct;33(7):875-82. doi: 10.1016/j.nucmedbio.2006.07.004.
• [9] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [10] Solvent effect on cDNA-expressed human sulfotransferase (SULT) activities in vitro. Drug Metab Dispos. 2003 Nov;31(11):1300-5.
• [11] In vitro and in vivo irinotecan-induced changes in expression profiles of cell cycle and apoptosis-associated genes in acute myeloid leukemia cells. Mol Cancer Ther. 2005 Jun;4(6):885-900.
• [12] Megadose vitamin C suppresses sulfoconjugation in human colon carcinoma cell line Caco-2. Toxicol In Vitro. 2011 Mar;25(2):500-4.
• [13] Identification by automated screening of a small molecule that selectively eliminates neural stem cells derived from hESCs but not dopamine neurons. PLoS One. 2009 Sep 23;4(9):e7155.
• [14] Benzo[a]pyrene and glycine N-methyltransferse interactions: gene expression profiles of the liver detoxification pathway. Toxicol Appl Pharmacol. 2006 Jul 15;214(2):126-35.
• [15] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [16] Environmental pollutant induced cellular injury is reflected in exosomes from placental explants. Placenta. 2020 Jan 1;89:42-49. doi: 10.1016/j.placenta.2019.10.008. Epub 2019 Oct 17.
• [17] 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.
• [18] Enzymatic characterization and interspecies difference of phenol sulfotransferases, ST1A forms. Drug Metab Dispos. 2001 Mar;29(3):274-81.
• [19] 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.
• [20] Sulfation of environmental estrogen-like chemicals by human cytosolic sulfotransferases. Biochem Biophys Res Commun. 2000 Jan 7;267(1):80-4. doi: 10.1006/bbrc.1999.1935.
• [21] Sulfotransferase 1E1 is a low km isoform mediating the 3-O-sulfation of ethinyl estradiol. Drug Metab Dispos. 2004 Nov;32(11):1299-303. doi: 10.1124/dmd.32.11..
• [22] 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.
• [23] Sulfation of benzyl alcohol by the human cytosolic sulfotransferases (SULTs): a systematic analysis. J Appl Toxicol. 2016 Sep;36(9):1090-4.
• [24] Cigarette smoke toxicants as substrates and inhibitors for human cytosolic SULTs. Toxicol Appl Pharmacol. 2007 May 15;221(1):13-20. doi: 10.1016/j.taap.2007.02.013. Epub 2007 Feb 28.
• [25] Sulfation of resveratrol in human liver: evidence of a major role for the sulfotransferases SULT1A1 and SULT1E1. Xenobiotica. 2005 Dec;35(12):1101-19. doi: 10.1080/00498250500354253.
• [26] Clioquinol is sulfated by human jejunum cytosol and SULT1A3, a human-specific dopamine sulfotransferase. Toxicol Lett. 2011 Oct 10;206(2):229-33.
• [27] Genetically modified Chinese hamster ovary cells for investigating sulfotransferase-mediated cytotoxicity and mutation by 2-amino-1-methyl-6- phenylimidazo[4,5-b]pyridine. Environ Mol Mutagen. 2000;35(1):57-65.