Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTKOR4F2)

• DOT Name: Sodium- and chloride-dependent betaine transporter (SLC6A12)
• Synonyms: BGT-1; Na(+)/Cl(-) betaine/GABA transporter; Solute carrier family 6 member 12
• Gene Name: SLC6A12
• UniProt ID: S6A12_HUMAN
• Pfam ID: PF00209
• Sequence:
  MDGKVAVQECGPPAVSWVPEEGEKLDQEDEDQVKDRGQWTNKMEFVLSVAGEIIGLGNVW
  RFPYLCYKNGGGAFFIPYFIFFFVCGIPVFFLEVALGQYTSQGSVTAWRKICPLFQGIGL
  ASVVIESYLNVYYIIILAWALFYLFSSFTSELPWTTCNNFWNTEHCTDFLNHSGAGTVTP
  FENFTSPVMEFWERRVLGITSGIHDLGSLRWELALCLLLAWVICYFCIWKGVKSTGKVVY
  FTATFPYLMLVILLIRGVTLPGAYQGIIYYLKPDLFRLKDPQVWMDAGTQIFFSFAICQG
  CLTALGSYNKYHNNCYKDCIALCFLNSATSFVAGFVVFSILGFMSQEQGVPISEVAESGP
  GLAFIAFPKAVTMMPLSQLWSCLFFIMLIFLGLDSQFVCVECLVTASIDMFPRQLRKSGR
  RELLILTIAVMCYLIGLFLVTEGGMYIFQLFDYYASSGICLLFLSLFEVVCISWVYGADR
  FYDNIEDMIGYRPWPLVKISWLFLTPGLCLATFLFSLSKYTPLKYNNVYVYPPWGYSIGW
  FLALSSMVCVPLFVVITLLKTRGPFRKRLRQLITPDSSLPQPKQHPCLDGSAGRNFGPSP
  TREGLIAGEKETHL
• Function: Transporter that mediates cellular uptake of betaine and GABA in a sodium- and chloride-dependent process. May have a role in regulation of GABAergic transmission in the brain through the reuptake of GABA into presynaptic terminals, as well as in osmotic regulation. Probably also involved in renal and hepatic osmotic regulation.
• Tissue Specificity: Expressed in kidney, liver, heart, skeletal muscle, placenta, and a widespread distribution in the brain.
• KEGG Pathway:
  Sy.ptic vesicle cycle (hsa04721)
  GABAergic sy.pse (hsa04727)
• Reactome Pathway:
  Na+/Cl- dependent neurotransmitter transporters (R-HSA-442660)
  Creatine metabolism (R-HSA-71288)
  Reuptake of GABA (R-HSA-888593)
  Amino acid transport across the plasma membrane (R-HSA-352230)

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Aspirin	DM672AH	Approved	Sodium- and chloride-dependent betaine transporter (SLC6A12) affects the response to substance of Aspirin.	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Sodium- and chloride-dependent betaine transporter (SLC6A12).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Sodium- and chloride-dependent betaine transporter (SLC6A12).	[2]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Sodium- and chloride-dependent betaine transporter (SLC6A12).	[3]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Sodium- and chloride-dependent betaine transporter (SLC6A12).	[4]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Sodium- and chloride-dependent betaine transporter (SLC6A12).	[2]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Sodium- and chloride-dependent betaine transporter (SLC6A12).	[5]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Sodium- and chloride-dependent betaine transporter (SLC6A12).	[6]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Sodium- and chloride-dependent betaine transporter (SLC6A12).	[7]
Rifampicin	DM5DSFZ	Approved	Rifampicin increases the expression of Sodium- and chloride-dependent betaine transporter (SLC6A12).	[8]
Zidovudine	DM4KI7O	Approved	Zidovudine increases the expression of Sodium- and chloride-dependent betaine transporter (SLC6A12).	[9]
Sodium chloride	DMM3950	Approved	Sodium chloride increases the expression of Sodium- and chloride-dependent betaine transporter (SLC6A12).	[10]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Sodium- and chloride-dependent betaine transporter (SLC6A12).	[11]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Sodium- and chloride-dependent betaine transporter (SLC6A12).	[13]
Hexadecanoic acid	DMWUXDZ	Investigative	Hexadecanoic acid increases the expression of Sodium- and chloride-dependent betaine transporter (SLC6A12).	[14]

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 decreases the methylation of Sodium- and chloride-dependent betaine transporter (SLC6A12).	[12]

References

• [1] 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.
• [2] 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.
• [3] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [4] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [5] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [6] Global effects of inorganic arsenic on gene expression profile in human macrophages. Mol Immunol. 2009 Feb;46(4):649-56.
• [7] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [8] Rifampin Regulation of Drug Transporters Gene Expression and the Association of MicroRNAs in Human Hepatocytes. Front Pharmacol. 2016 Apr 26;7:111.
• [9] Differential gene expression in human hepatocyte cell lines exposed to the antiretroviral agent zidovudine. Arch Toxicol. 2014 Mar;88(3):609-23. doi: 10.1007/s00204-013-1169-3. Epub 2013 Nov 30.
• [10] Mitochondrial reactive oxygen species contribute to high NaCl-induced activation of the transcription factor TonEBP/OREBP. Am J Physiol Renal Physiol. 2006 May;290(5):F1169-76. doi: 10.1152/ajprenal.00378.2005. Epub 2005 Nov 22.
• [11] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [12] 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.
• [13] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [14] Direct effect of 2-palmitoyl glycerol on promotion of gamma aminobutyric acid synthesis in normal human fetal-derived astrocytes. FEBS Open Bio. 2023 Jul;13(7):1320-1332. doi: 10.1002/2211-5463.13649. Epub 2023 May 24.
• [15] Association of SLC6A12 variants with aspirin-intolerant asthma in a Korean population. Ann Hum Genet. 2010 Jul;74(4):326-34.