Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT67U7G3)

• DOT Name: Sodium- and chloride-dependent taurine transporter (SLC6A6)
• Synonyms: Solute carrier family 6 member 6
• Gene Name: SLC6A6
• Related Disease: Hypotaurinemic retinal degeneration and cardiomyopathy
• UniProt ID: SC6A6_HUMAN
• Pfam ID: PF00209
• Sequence:
  MATKEKLQCLKDFHKDILKPSPGKSPGTRPEDEAEGKPPQREKWSSKIDFVLSVAGGFVG
  LGNVWRFPYLCYKNGGGAFLIPYFIFLFGSGLPVFFLEIIIGQYTSEGGITCWEKICPLF
  SGIGYASVVIVSLLNVYYIVILAWATYYLFQSFQKELPWAHCNHSWNTPHCMEDTMRKNK
  SVWITISSTNFTSPVIEFWERNVLSLSPGIDHPGSLKWDLALCLLLVWLVCFFCIWKGVR
  STGKVVYFTATFPFAMLLVLLVRGLTLPGAGAGIKFYLYPDITRLEDPQVWIDAGTQIFF
  SYAICLGAMTSLGSYNKYKYNSYRDCMLLGCLNSGTSFVSGFAIFSILGFMAQEQGVDIA
  DVAESGPGLAFIAYPKAVTMMPLPTFWSILFFIMLLLLGLDSQFVEVEGQITSLVDLYPS
  FLRKGYRREIFIAFVCSISYLLGLTMVTEGGMYVFQLFDYYAASGVCLLWVAFFECFVIA
  WIYGGDNLYDGIEDMIGYRPGPWMKYSWAVITPVLCVGCFIFSLVKYVPLTYNKTYVYPN
  WAIGLGWSLALSSMLCVPLVIVIRLCQTEGPFLVRVKYLLTPREPNRWAVEREGATPYNS
  RTVMNGALVKPTHIIVETMM
• Function: Mediates sodium- and chloride-dependent transport of taurine. Mediates transport of beta-alanine. Can also mediate transport of hypotaurine and gamma-aminobutyric acid (GABA); Sodium-dependent taurine and beta-alanine transporter. Chloride ions are necessary for optimal uptake.
• Tissue Specificity: Expressed abundantly in placenta and skeletal muscle, at intermediate levels in heart, brain, lung, kidney and pancreas and at low levels in liver.
• Reactome Pathway:
  Na+/Cl- dependent neurotransmitter transporters (R-HSA-442660)
  Amino acid transport across the plasma membrane (R-HSA-352230)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hypotaurinemic retinal degeneration and cardiomyopathy	DIS7UKI2	Limited	Autosomal recessive	[1]

5 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 Sodium- and chloride-dependent taurine transporter (SLC6A6).	[2]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Sodium- and chloride-dependent taurine transporter (SLC6A6).	[9]
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of Sodium- and chloride-dependent taurine transporter (SLC6A6).	[13]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Sodium- and chloride-dependent taurine transporter (SLC6A6).	[19]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Sodium- and chloride-dependent taurine transporter (SLC6A6).	[13]

19 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 Sodium- and chloride-dependent taurine transporter (SLC6A6).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Sodium- and chloride-dependent taurine transporter (SLC6A6).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Sodium- and chloride-dependent taurine transporter (SLC6A6).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Sodium- and chloride-dependent taurine transporter (SLC6A6).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Sodium- and chloride-dependent taurine transporter (SLC6A6).	[7]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Sodium- and chloride-dependent taurine transporter (SLC6A6).	[8]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Sodium- and chloride-dependent taurine transporter (SLC6A6).	[10]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Sodium- and chloride-dependent taurine transporter (SLC6A6).	[11]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Sodium- and chloride-dependent taurine transporter (SLC6A6).	[12]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol increases the expression of Sodium- and chloride-dependent taurine transporter (SLC6A6).	[14]
Azathioprine	DMMZSXQ	Approved	Azathioprine increases the expression of Sodium- and chloride-dependent taurine transporter (SLC6A6).	[15]
Dasatinib	DMJV2EK	Approved	Dasatinib increases the expression of Sodium- and chloride-dependent taurine transporter (SLC6A6).	[16]
Amphotericin B	DMTAJQE	Approved	Amphotericin B decreases the expression of Sodium- and chloride-dependent taurine transporter (SLC6A6).	[17]
Ethinyl estradiol	DMODJ40	Approved	Ethinyl estradiol decreases the expression of Sodium- and chloride-dependent taurine transporter (SLC6A6).	[18]
Cidofovir	DMA13GD	Approved	Cidofovir affects the expression of Sodium- and chloride-dependent taurine transporter (SLC6A6).	[3]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Sodium- and chloride-dependent taurine transporter (SLC6A6).	[14]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Sodium- and chloride-dependent taurine transporter (SLC6A6).	[20]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Sodium- and chloride-dependent taurine transporter (SLC6A6).	[21]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane increases the expression of Sodium- and chloride-dependent taurine transporter (SLC6A6).	[22]

References

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• [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] Transcriptomics hit the target: monitoring of ligand-activated and stress response pathways for chemical testing. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):7-18.
• [4] Retinoic acid receptor alpha amplifications and retinoic acid sensitivity in breast cancers. Clin Breast Cancer. 2013 Oct;13(5):401-8.
• [5] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [8] Bisphenol-A and estradiol exert novel gene regulation in human MCF-7 derived breast cancer cells. Mol Cell Endocrinol. 2004 Jun 30;221(1-2):47-55. doi: 10.1016/j.mce.2004.04.010.
• [9] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [10] 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.
• [11] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [12] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [13] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [14] Gene expression profiling in Ishikawa cells: a fingerprint for estrogen active compounds. Toxicol Appl Pharmacol. 2009 Apr 1;236(1):85-96.
• [15] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.
• [16] 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.
• [17] Differential expression of microRNAs and their predicted targets in renal cells exposed to amphotericin B and its complex with copper (II) ions. Toxicol Mech Methods. 2017 Sep;27(7):537-543. doi: 10.1080/15376516.2017.1333554. Epub 2017 Jun 8.
• [18] The genomic response of a human uterine endometrial adenocarcinoma cell line to 17alpha-ethynyl estradiol. Toxicol Sci. 2009 Jan;107(1):40-55.
• [19] 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.
• [20] 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.
• [21] 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.
• [22] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.