Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT727K92)

• DOT Name: Electrogenic sodium bicarbonate cotransporter 1 (SLC4A4)
• Synonyms: Sodium bicarbonate cotransporter; Na(+)/HCO3(-) cotransporter; Solute carrier family 4 member 4; kNBC1
• Gene Name: SLC4A4
• Related Disease: Autosomal recessive proximal renal tubular acidosis
• UniProt ID: S4A4_HUMAN
• PDB ID: 6CAA
• Pfam ID: PF07565 ; PF00955
• Sequence:
  MEDEAVLDRGASFLKHVCDEEEVEGHHTIYIGVHVPKSYRRRRRHKRKTGHKEKKEKERI
  SENYSDKSDIENADESSSSILKPLISPAAERIRFILGEEDDSPAPPQLFTELDELLAVDG
  QEMEWKETARWIKFEEKVEQGGERWSKPHVATLSLHSLFELRTCMEKGSIMLDREASSLP
  QLVEMIVDHQIETGLLKPELKDKVTYTLLRKHRHQTKKSNLRSLADIGKTVSSASRMFTN
  PDNGSPAMTHRNLTSSSLNDISDKPEKDQLKNKFMKKLPRDAEASNVLVGEVDFLDTPFI
  AFVRLQQAVMLGALTEVPVPTRFLFILLGPKGKAKSYHEIGRAIATLMSDEVFHDIAYKA
  KDRHDLIAGIDEFLDEVIVLPPGEWDPAIRIEPPKSLPSSDKRKNMYSGGENVQMNGDTP
  HDGGHGGGGHGDCEELQRTGRFCGGLIKDIKRKAPFFASDFYDALNIQALSAILFIYLAT
  VTNAITFGGLLGDATDNMQGVLESFLGTAVSGAIFCLFAGQPLTILSSTGPVLVFERLLF
  NFSKDNNFDYLEFRLWIGLWSAFLCLILVATDASFLVQYFTRFTEEGFSSLISFIFIYDA
  FKKMIKLADYYPINSNFKVGYNTLFSCTCVPPDPANISISNDTTLAPEYLPTMSSTDMYH
  NTTFDWAFLSKKECSKYGGNLVGNNCNFVPDITLMSFILFLGTYTSSMALKKFKTSPYFP
  TTARKLISDFAIILSILIFCVIDALVGVDTPKLIVPSEFKPTSPNRGWFVPPFGENPWWV
  CLAAAIPALLVTILIFMDQQITAVIVNRKEHKLKKGAGYHLDLFWVAILMVICSLMALPW
  YVAATVISIAHIDSLKMETETSAPGEQPKFLGVREQRVTGTLVFILTGLSVFMAPILKFI
  PMPVLYGVFLYMGVASLNGVQFMDRLKLLLMPLKHQPDFIYLRHVPLRRVHLFTFLQVLC
  LALLWILKSTVAAIIFPVMILALVAVRKGMDYLFSQHDLSFLDDVIPEKDKKKKEDEKKK
  KKKKGSLDSDNDDSDCPYSEKVPSIKIPMDIMEQQPFLSDSKPSDRERSPTFLERHTSC
• Function: Electrogenic sodium/bicarbonate cotransporter with a Na(+):HCO3(-) stoichiometry varying from 1:2 to 1:3. May regulate bicarbonate influx/efflux at the basolateral membrane of cells and regulate intracellular pH.
• Tissue Specificity: .Expressed in the corneal endothelium cells (at protein level). Expressed in pancreas and to a lower extent in heart, skeletal muscle, liver, parotid salivary glands, prostate, colon, stomach, thyroid, brain and spinal chord.; [Isoform 2]: Specifically expressed in kidney at the level of proximal tubules.
• KEGG Pathway:
  Proximal tubule bicarbo.te reclamation (hsa04964)
  Pancreatic secretion (hsa04972)
  Bile secretion (hsa04976)
• Reactome Pathway:
  Defective SLC4A4 causes renal tubular acidosis, proximal, with ocular abnormalities and mental retardation (pRTA-OA) (R-HSA-5619054)
  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
Autosomal recessive proximal renal tubular acidosis	DISY3SSY	Definitive	Autosomal recessive	[1]

This DOT Affected the Regulation of Drug Effects of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Sodium bicarbonate	DMMU6BJ	Approved	Electrogenic sodium bicarbonate cotransporter 1 (SLC4A4) increases the transport of Sodium bicarbonate.	[16]
AMG 386	DMQJXL4	Phase 3	Electrogenic sodium bicarbonate cotransporter 1 (SLC4A4) increases the transport of AMG 386.	[16]

16 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 Electrogenic sodium bicarbonate cotransporter 1 (SLC4A4).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Electrogenic sodium bicarbonate cotransporter 1 (SLC4A4).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Electrogenic sodium bicarbonate cotransporter 1 (SLC4A4).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Electrogenic sodium bicarbonate cotransporter 1 (SLC4A4).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Electrogenic sodium bicarbonate cotransporter 1 (SLC4A4).	[6]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Electrogenic sodium bicarbonate cotransporter 1 (SLC4A4).	[8]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Electrogenic sodium bicarbonate cotransporter 1 (SLC4A4).	[9]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of Electrogenic sodium bicarbonate cotransporter 1 (SLC4A4).	[10]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Electrogenic sodium bicarbonate cotransporter 1 (SLC4A4).	[11]
Bicalutamide	DMZMSPF	Approved	Bicalutamide decreases the expression of Electrogenic sodium bicarbonate cotransporter 1 (SLC4A4).	[12]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Electrogenic sodium bicarbonate cotransporter 1 (SLC4A4).	[13]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Electrogenic sodium bicarbonate cotransporter 1 (SLC4A4).	[11]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Electrogenic sodium bicarbonate cotransporter 1 (SLC4A4).	[14]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Electrogenic sodium bicarbonate cotransporter 1 (SLC4A4).	[15]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Electrogenic sodium bicarbonate cotransporter 1 (SLC4A4).	[2]
G418	DMKTJBU	Investigative	G418 increases the expression of Electrogenic sodium bicarbonate cotransporter 1 (SLC4A4).	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic increases the methylation of Electrogenic sodium bicarbonate cotransporter 1 (SLC4A4).	[7]

References

• [1] Mutations in SLC4A4 cause permanent isolated proximal renal tubular acidosis with ocular abnormalities. Nat Genet. 1999 Nov;23(3):264-6. doi: 10.1038/15440.
• [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] 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.
• [4] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [5] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [6] 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.
• [7] Gene-specific differential DNA methylation and chronic arsenic exposure in an epigenome-wide association study of adults in Bangladesh. Environ Health Perspect. 2015 Jan;123(1):64-71. doi: 10.1289/ehp.1307884. Epub 2014 Oct 17.
• [8] 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.
• [9] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [10] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [11] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [12] Microarray analysis of bicalutamide action on telomerase activity, p53 pathway and viability of prostate carcinoma cell lines. J Pharm Pharmacol. 2005 Jan;57(1):83-92.
• [13] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [14] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [15] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [16] G418-mediated ribosomal read-through of a nonsense mutation causing autosomal recessive proximal renal tubular acidosis. Am J Physiol Renal Physiol. 2008 Sep;295(3):F633-41. doi: 10.1152/ajprenal.00015.2008. Epub 2008 Jul 9.