Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTHJP5FU)

• DOT Name: Solute carrier family 12 member 8 (SLC12A8)
• Synonyms: Cation-chloride cotransporter 9
• Gene Name: SLC12A8
• UniProt ID: S12A8_HUMAN
• Pfam ID: PF00324
• Sequence:
  MTQMSQVQELFHEAAQQDALAQPQPWWKTQLFMWEPVLFGTWDGVFTSCMINIFGVVLFL
  RTGWLVGNTGVLLGMFLVSFVILVALVTVLSGIGVGERSSIGSGGVYSMISSVLGGQTGG
  TIGLLYVFGQCVAGAMYITGFAESISDLLGLGNIWAVRGISVAVLLALLGINLAGVKWII
  RLQLLLLFLLAVSTLDFVVGSFTHLDPEHGFIGYSPELLQNNTLPDYSPGESFFTVFGVF
  FPAATGVMAGFNMGGDLREPAASIPLGSLAAVGISWFLYIIFVFLLGAICTREALRYDFL
  IAEKVSLMGFLFLLGLYISSLASCMGGLYGAPRILQCIAQEKVIPALACLGQGKGPNKTP
  VAAICLTSLVTMAFVFVGQVNVLAPIVTINFMLTYVAVDYSYFSLSMCSCSLTPVPEPVL
  REGAEGLHCSEHLLLEKAPSYGSEGPAQRVLEGTLLEFTKDMDQLLQLTRKLESSQPRQG
  EGNRTPESQKRKSKKATKQTLQDSFLLDLKSPPSFPVEISDRLPAASWEGQESCWNKQTS
  KSEGTQPEGTYGEQLVPELCNQSESSGEDFFLKSRLQEQDVWRRSTSFYTHMCNPWVSLL
  GAVGSLLIMFVIQWVYTLVNMGVAAIVYFYIGRASPGLHLGSASNFSFFRWMRSLLLPSC
  RSLRSPQEQIILAPSLAKVDMEMTQLTQENADFATRDRYHHSSLVNREQLMPHY
• Function: Cation/chloride cotransporter that may play a role in the control of keratinocyte proliferation.
• Tissue Specificity: Ubiquitous with very low level in normal skin.

Molecular Interaction Atlas (MIA) of This DOT

18 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 Solute carrier family 12 member 8 (SLC12A8).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Solute carrier family 12 member 8 (SLC12A8).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Solute carrier family 12 member 8 (SLC12A8).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Solute carrier family 12 member 8 (SLC12A8).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Solute carrier family 12 member 8 (SLC12A8).	[5]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Solute carrier family 12 member 8 (SLC12A8).	[6]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Solute carrier family 12 member 8 (SLC12A8).	[7]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide decreases the expression of Solute carrier family 12 member 8 (SLC12A8).	[8]
Cidofovir	DMA13GD	Approved	Cidofovir affects the expression of Solute carrier family 12 member 8 (SLC12A8).	[5]
Ifosfamide	DMCT3I8	Approved	Ifosfamide decreases the expression of Solute carrier family 12 member 8 (SLC12A8).	[5]
Clodronate	DM9Y6X7	Approved	Clodronate decreases the expression of Solute carrier family 12 member 8 (SLC12A8).	[5]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Solute carrier family 12 member 8 (SLC12A8).	[9]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Solute carrier family 12 member 8 (SLC12A8).	[11]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Solute carrier family 12 member 8 (SLC12A8).	[12]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Solute carrier family 12 member 8 (SLC12A8).	[6]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane increases the expression of Solute carrier family 12 member 8 (SLC12A8).	[14]
GALLICACID	DM6Y3A0	Investigative	GALLICACID decreases the expression of Solute carrier family 12 member 8 (SLC12A8).	[15]
Lead acetate	DML0GZ2	Investigative	Lead acetate increases the expression of Solute carrier family 12 member 8 (SLC12A8).	[16]

2 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 Solute carrier family 12 member 8 (SLC12A8).	[10]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Solute carrier family 12 member 8 (SLC12A8).	[13]

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] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [4] 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.
• [5] 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.
• [6] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [7] 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.
• [8] Oxidative stress modulates theophylline effects on steroid responsiveness. Biochem Biophys Res Commun. 2008 Dec 19;377(3):797-802.
• [9] 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.
• [10] 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.
• [11] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [12] 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.
• [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] 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.
• [15] Gene expression profile analysis of gallic acid-induced cell death process. Sci Rep. 2021 Aug 18;11(1):16743. doi: 10.1038/s41598-021-96174-1.
• [16] Analysis of lead toxicity in human cells. BMC Genomics. 2012 Jul 27;13:344.