Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTKJ0X6Q)

• DOT Name: Electroneutral sodium bicarbonate exchanger 1 (SLC4A8)
• Synonyms: Electroneutral Na(+)-driven Cl-HCO3 exchanger; Solute carrier family 4 member 8; k-NBC3
• Gene Name: SLC4A8
• Related Disease: Schizophrenia
• UniProt ID: S4A8_HUMAN
• PDB ID: 5JHO
• Pfam ID: PF07565 ; PF00955
• Sequence:
  MPAAGSNEPDGVLSYQRPDEEAVVDQGGTSTILNIHYEKEELEGHRTLYVGVRMPLGRQS
  HRHHRTHGQKHRRRGRGKGASQGEEGLEALAHDTPSQRVQFILGTEEDEEHVPHELFTEL
  DEICMKEGEDAEWKETARWLKFEEDVEDGGERWSKPYVATLSLHSLFELRSCLINGTVLL
  DMHANSIEEISDLILDQQELSSDLNDSMRVKVREALLKKHHHQNEKKRNNLIPIVRSFAE
  VGKKQSDPHLMDKHGQTVSPQSVPTTNLEVKNGVNCEHSPVDLSKVDLHFMKKIPTGAEA
  SNVLVGEVDILDRPIVAFVRLSPAVLLSGLTEVPIPTRFLFILLGPVGKGQQYHEIGRSM
  ATIMTDEIFHDVAYKAKERDDLLAGIDEFLDQVTVLPPGEWDPSIRIEPPKNVPSQEKRK
  MPGVPNGNVCHIEQEPHGGHSGPELQRTGRLFGGLVLDIKRKAPWYWSDYRDALSLQCLA
  SFLFLYCACMSPVITFGGLLGEATEGRISAIESLFGASMTGIAYSLFAGQALTILGSTGP
  VLVFEKILFKFCKDYALSYLSLRACIGLWTAFLCIVLVATDASSLVCYITRFTEEAFASL
  ICIIFIYEAIEKLIHLAETYPIHMHSQLDHLSLYYCRCTLPENPNNHTLQYWKDHNIVTA
  EVHWANLTVSECQEMHGEFMGSACGHHGPYTPDVLFWSCILFFTTFILSSTLKTFKTSRY
  FPTRVRSMVSDFAVFLTIFTMVIIDFLIGVPSPKLQVPSVFKPTRDDRGWIINPIGPNPW
  WTVIAAIIPALLCTILIFMDQQITAVIINRKEHKLKKGCGYHLDLLMVAIMLGVCSIMGL
  PWFVAATVLSITHVNSLKLESECSAPGEQPKFLGIREQRVTGLMIFVLMGCSVFMTAILK
  FIPMPVLYGVFLYMGVSSLQGIQFFDRLKLFGMPAKHQPDFIYLRHVPLRKVHLFTLIQL
  TCLVLLWVIKASPAAIVFPMMVLALVFVRKVMDLCFSKRELSWLDDLMPESKKKKLDDAK
  KKAKEEEEAEKMLEIGGDKFPLESRKLLSSPGKNISCRCDPSEINISDEMPKTTVWKALS
  MNSGNAKEKSLFN
• Function: Mediates electroneutral sodium- and carbonate-dependent chloride-HCO3(-) exchange with a Na(+):HCO3(-) stoichiometry of 2:1. Plays a major role in pH regulation in neurons. Mediates sodium reabsorption in the renal cortical collecting ducts.
• Tissue Specificity: Expressed in the pyramidal cells of the hippocampus (at protein level). Highly expressed in all major regions of the brain, spinal column and in testis, and moderate levels in trachea, thyroid and medulla region of kidney. Low expression levels observed in pancreas and kidney cortex.; [Isoform 1]: Expressed in the brain.; [Isoform 4]: Expressed in the brain, heart and kidney.; [Isoform 5]: Expressed in the brain, heart and kidney.
• Reactome Pathway: Bicarbonate transporters (R-HSA-425381)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Schizophrenia	DISSRV2N	Limited	Unknown	[1]

11 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 Electroneutral sodium bicarbonate exchanger 1 (SLC4A8).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Electroneutral sodium bicarbonate exchanger 1 (SLC4A8).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Electroneutral sodium bicarbonate exchanger 1 (SLC4A8).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Electroneutral sodium bicarbonate exchanger 1 (SLC4A8).	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Electroneutral sodium bicarbonate exchanger 1 (SLC4A8).	[6]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Electroneutral sodium bicarbonate exchanger 1 (SLC4A8).	[7]
Cytarabine	DMZD5QR	Approved	Cytarabine decreases the expression of Electroneutral sodium bicarbonate exchanger 1 (SLC4A8).	[8]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Electroneutral sodium bicarbonate exchanger 1 (SLC4A8).	[10]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Electroneutral sodium bicarbonate exchanger 1 (SLC4A8).	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Electroneutral sodium bicarbonate exchanger 1 (SLC4A8).	[12]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Electroneutral sodium bicarbonate exchanger 1 (SLC4A8).	[13]

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 increases the methylation of Electroneutral sodium bicarbonate exchanger 1 (SLC4A8).	[9]

References

• [1] De novo gene mutations highlight patterns of genetic and neural complexity in schizophrenia. Nat Genet. 2012 Dec;44(12):1365-9. doi: 10.1038/ng.2446. Epub 2012 Oct 3.
• [2] 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.
• [3] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [4] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [5] 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.
• [6] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [7] Differential regulation of native estrogen receptor-regulatory elements by estradiol, tamoxifen, and raloxifene. Mol Endocrinol. 2008 Feb;22(2):287-303. doi: 10.1210/me.2007-0340. Epub 2007 Oct 25.
• [8] Cytosine arabinoside induces ectoderm and inhibits mesoderm expression in human embryonic stem cells during multilineage differentiation. Br J Pharmacol. 2011 Apr;162(8):1743-56.
• [9] 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.
• [10] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [11] 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.
• [12] Bisphenol A and bisphenol S induce distinct transcriptional profiles in differentiating human primary preadipocytes. PLoS One. 2016 Sep 29;11(9):e0163318.
• [13] 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.