Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTBNK2U2)

• DOT Name: Chloride anion exchanger (SLC26A3)
• Synonyms: Down-regulated in adenoma; Protein DRA; Solute carrier family 26 member 3
• Gene Name: SLC26A3
• Related Disease: Congenital secretory chloride diarrhea 1
• UniProt ID: S26A3_HUMAN
• PDB ID: 7XUH; 7XUJ; 7XUL
• Pfam ID: PF01740 ; PF00916
• Sequence:
  MIEPFGNQYIVARPVYSTNAFEENHKKTGRHHKTFLDHLKVCCSCSPQKAKRIVLSLFPI
  ASWLPAYRLKEWLLSDIVSGISTGIVAVLQGLAFALLVDIPPVYGLYASFFPAIIYLFFG
  TSRHISVGPFPILSMMVGLAVSGAVSKAVPDRNATTLGLPNNSNNSSLLDDERVRVAAAA
  SVTVLSGIIQLAFGILRIGFVVIYLSESLISGFTTAAAVHVLVSQLKFIFQLTVPSHTDP
  VSIFKVLYSVFSQIEKTNIADLVTALIVLLVVSIVKEINQRFKDKLPVPIPIEFIMTVIA
  AGVSYGCDFKNRFKVAVVGDMNPGFQPPITPDVETFQNTVGDCFGIAMVAFAVAFSVASV
  YSLKYDYPLDGNQELIALGLGNIVCGVFRGFAGSTALSRSAVQESTGGKTQIAGLIGAII
  VLIVVLAIGFLLAPLQKSVLAALALGNLKGMLMQFAEIGRLWRKDKYDCLIWIMTFIFTI
  VLGLGLGLAASVAFQLLTIVFRTQFPKCSTLANIGRTNIYKNKKDYYDMYEPEGVKIFRC
  PSPIYFANIGFFRRKLIDAVGFSPLRILRKRNKALRKIRKLQKQGLLQVTPKGFICTVDT
  IKDSDEELDNNQIEVLDQPINTTDLPFHIDWNDDLPLNIEVPKISLHSLILDFSAVSFLD
  VSSVRGLKSILQEFIRIKVDVYIVGTDDDFIEKLNRYEFFDGEVKSSIFFLTIHDAVLHI
  LMKKDYSTSKFNPSQEKDGKIDFTINTNGGLRNRVYEVPVETKF
• Function: Mediates chloride-bicarbonate exchange with a chloride bicarbonate stoichiometry of 2:1 in the intestinal epithelia. Plays a role in the chloride and bicarbonate homeostasis during sperm epididymal maturation and capacitation.
• Tissue Specificity: Expressed in the colon. Expression is significantly decreased in adenomas (polyps) and adenocarcinomas of the colon.
• KEGG Pathway:
  Pancreatic secretion (hsa04972)
  Mineral absorption (hsa04978)
• Reactome Pathway:
  Defective SLC26A3 causes congenital secretory chloride diarrhea 1 (DIAR1) (R-HSA-5619085)
  Multifunctional anion exchangers (R-HSA-427601)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Congenital secretory chloride diarrhea 1	DIS4DK4B	Definitive	Autosomal recessive	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Chloride	DM1TJXA	Phase 3	Chloride anion exchanger (SLC26A3) affects the transport of Chloride.	[10]
Bicarbonate	DMT5E36	Investigative	Chloride anion exchanger (SLC26A3) affects the transport of Bicarbonate.	[10]

14 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 Chloride anion exchanger (SLC26A3).	[2]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Chloride anion exchanger (SLC26A3).	[2]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Chloride anion exchanger (SLC26A3).	[3]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Chloride anion exchanger (SLC26A3).	[4]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Chloride anion exchanger (SLC26A3).	[4]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Chloride anion exchanger (SLC26A3).	[5]
Folic acid	DMEMBJC	Approved	Folic acid increases the expression of Chloride anion exchanger (SLC26A3).	[6]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Chloride anion exchanger (SLC26A3).	[7]
Zidovudine	DM4KI7O	Approved	Zidovudine decreases the expression of Chloride anion exchanger (SLC26A3).	[8]
Capecitabine	DMTS85L	Approved	Capecitabine increases the expression of Chloride anion exchanger (SLC26A3).	[9]
Morniflumate	DM9UTDE	Approved	Morniflumate decreases the activity of Chloride anion exchanger (SLC26A3).	[10]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Chloride anion exchanger (SLC26A3).	[11]
Tenidap	DMHQRYE	Phase 3	Tenidap decreases the activity of Chloride anion exchanger (SLC26A3).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the mutagenesis of Chloride anion exchanger (SLC26A3).	[12]

References

• [1] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [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] 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.
• [4] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [5] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [6] Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
• [7] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [8] 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.
• [9] Gene expression responses reflecting 5-FU-induced toxicity: Comparison between patient colon tissue and 3D human colon organoids. Toxicol Lett. 2022 Dec 1;371:17-24. doi: 10.1016/j.toxlet.2022.09.013. Epub 2022 Sep 29.
• [10] Acute regulation of the SLC26A3 congenital chloride diarrhoea anion exchanger (DRA) expressed in Xenopus oocytes. J Physiol. 2003 May 15;549(Pt 1):3-19. doi: 10.1113/jphysiol.2003.039818. Epub 2003 Mar 21.
• [11] 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.
• [12] Exome-wide mutation profile in benzo[a]pyrene-derived post-stasis and immortal human mammary epithelial cells. Mutat Res Genet Toxicol Environ Mutagen. 2014 Dec;775-776:48-54. doi: 10.1016/j.mrgentox.2014.10.011. Epub 2014 Nov 4.