Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTKY9NAL)

• DOT Name: Sodium-coupled monocarboxylate transporter 2 (SLC5A12)
• Synonyms: Electroneutral sodium monocarboxylate cotransporter; Low-affinity sodium-lactate cotransporter; Solute carrier family 5 member 12
• Gene Name: SLC5A12
• UniProt ID: SC5AC_HUMAN
• Pfam ID: PF00474
• Sequence:
  MEVKNFAVWDYVVFAALFFISSGIGVFFAIKERKKATSREFLVGGRQMSFGPVGLSLTAS
  FMSAVTVLGTPSEVYRFGASFLVFFIAYLFVILLTSELFLPVFYRSGITSTYEYLQLRFN
  KPVRYAATVIYIVQTILYTGVVVYAPALALNQVTGFDLWGSVFATGIVCTFYCTLGGLKA
  VVWTDAFQMVVMIVGFLTVLIQGSTHAGGFHNVLEQSTNGSRLHIFDFDVDPLRRHTFWT
  ITVGGTFTWLGIYGVNQSTIQRCISCKTEKHAKLALYFNLLGLWIILVCAVFSGLIMYSH
  FKDCDPWTSGIISAPDQLMPYFVMEIFATMPGLPGLFVACAFSGTLSTVASSINALATVT
  FEDFVKSCFPHLSDKLSTWISKGLCLLFGVMCTSMAVAASVMGGVVQASLSIHGMCGGPM
  LGLFSLGIVFPFVNWKGALGGLLTGITLSFWVAIGAFIYPAPASKTWPLPLSTDQCIKSN
  VTATGPPVLSSRPGIADTWYSISYLYYSAVGCLGCIVAGVIISLITGRQRGEDIQPLLIR
  PVCNLFCFWSKKYKTLCWCGVQHDSGTEQENLENGSARKQGAESVLQNGLRRESLVHVPG
  YDPKDKSYNNMAFETTHF
• Function: Acts as an electroneutral and low-affinity sodium (Na(+))-dependent sodium-coupled solute transporter. Catalyzes the transport across the plasma membrane of many monocarboxylates such as lactate, pyruvate, nicotinate, propionate, butyrate and beta-D-hydroxybutyrate. May be responsible for the first step of reabsorption of monocarboxylates from the lumen of the proximal tubule of the kidney and the small intestine. May play also a role in monocarboxylates transport in the retina.
• Reactome Pathway: Multifunctional anion exchangers (R-HSA-427601)

Molecular Interaction Atlas (MIA) of This DOT

10 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-coupled monocarboxylate transporter 2 (SLC5A12).	[1]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Sodium-coupled monocarboxylate transporter 2 (SLC5A12).	[2]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Sodium-coupled monocarboxylate transporter 2 (SLC5A12).	[3]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Sodium-coupled monocarboxylate transporter 2 (SLC5A12).	[4]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Sodium-coupled monocarboxylate transporter 2 (SLC5A12).	[5]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Sodium-coupled monocarboxylate transporter 2 (SLC5A12).	[6]
Folic acid	DMEMBJC	Approved	Folic acid increases the expression of Sodium-coupled monocarboxylate transporter 2 (SLC5A12).	[7]
Cytarabine	DMZD5QR	Approved	Cytarabine decreases the expression of Sodium-coupled monocarboxylate transporter 2 (SLC5A12).	[8]
Rifampicin	DM5DSFZ	Approved	Rifampicin increases the expression of Sodium-coupled monocarboxylate transporter 2 (SLC5A12).	[9]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Sodium-coupled monocarboxylate transporter 2 (SLC5A12).	[11]

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 Sodium-coupled monocarboxylate transporter 2 (SLC5A12).	[10]

References

• [1] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [2] RNA sequence analysis of inducible pluripotent stem cell-derived cardiomyocytes reveals altered expression of DNA damage and cell cycle genes in response to doxorubicin. Toxicol Appl Pharmacol. 2018 Oct 1;356:44-53.
• [3] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [4] Arsenic suppresses gene expression in promyelocytic leukemia cells partly through Sp1 oxidation. Blood. 2005 Jul 1;106(1):304-10.
• [5] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [6] 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.
• [7] 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.
• [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] Rifampin Regulation of Drug Transporters Gene Expression and the Association of MicroRNAs in Human Hepatocytes. Front Pharmacol. 2016 Apr 26;7:111.
• [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] 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.