Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTF2CNRD)

• DOT Name: Multidrug and toxin extrusion protein 2 (SLC47A2)
• Synonyms: MATE-2; hMATE-2; Kidney-specific H(+)/organic cation antiporter; Solute carrier family 47 member 2
• Gene Name: SLC47A2
• UniProt ID: S47A2_HUMAN
• Pfam ID: PF01554
• Sequence:
  MDSLQDTVALDHGGCCPALSRLVPRGFGTEMWTLFALSGPLFLFQVLTFMIYIVSTVFCG
  HLGKVELASVTLAVAFVNVCGVSVGVGLSSACDTLMSQSFGSPNKKHVGVILQRGALVLL
  LCCLPCWALFLNTQHILLLFRQDPDVSRLTQDYVMIFIPGLPVIFLYNLLAKYLQNQGWL
  KGQEEESPFQTPGLSILHPSHSHLSRASFHLFQKITWPQVLSGVVGNCVNGVANYALVSV
  LNLGVRGSAYANIISQFAQTVFLLLYIVLKKLHLETWAGWSSQCLQDWGPFFSLAVPSML
  MICVEWWAYEIGSFLMGLLSVVDLSAQAVIYEVATVTYMIPLGLSIGVCVRVGMALGAAD
  TVQAKRSAVSGVLSIVGISLVLGTLISILKNQLGHIFTNDEDVIALVSQVLPVYSVFHVF
  EAICCVYGGVLRGTGKQAFGAAVNAITYYIIGLPLGILLTFVVRMRIMGLWLGMLACVFL
  ATAAFVAYTARLDWKLAAEEAKKHSGRQQQQRAESTATRPGPEKAVLSSVATGSSPGITL
  TTYSRSECHVDFFRTPEEAHALSAPTSRLSVKQLVIRRGAALGAASATLMVGLTVRILAT
  RH
• Function: Multidrug efflux pump that functions as a H(+)/organic cation antiporter. Mediates the efflux of cationic compounds, such as the model cations, tetraethylammonium (TEA) and 1-methyl-4-phenylpyridinium (MPP+), the platinum-based drug oxaliplatin or weak bases that are positively charged at physiological pH, cimetidine, the platinum-based drugs cisplatin and oxaliplatin or the antidiabetic drug metformin. Mediates the efflux of endogenous compounds such as, creatinine, thiamine and estrone-3-sulfate. Plays a physiological role in the excretion of drugs, toxins and endogenous metabolites through the kidney; [Isoform 6]: Non-functional protein.
• Tissue Specificity: .High expression in kidney. Very small expression in adrenal gland and lung.; [Isoform 3]: High expression in kidney. Very small expression in brain and testis.; [Isoform 6]: Ubiquitously expressed in all tissues examined except the kidney.
• Reactome Pathway: Transport of bile salts and organic acids, metal ions and amine compounds (R-HSA-425366)

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Multidrug and toxin extrusion protein 2 (SLC47A2).	[1]

8 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 Multidrug and toxin extrusion protein 2 (SLC47A2).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Multidrug and toxin extrusion protein 2 (SLC47A2).	[3]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Multidrug and toxin extrusion protein 2 (SLC47A2).	[4]
Cannabidiol	DM0659E	Approved	Cannabidiol decreases the expression of Multidrug and toxin extrusion protein 2 (SLC47A2).	[5]
Pyrimethamine	DM5X7VY	Approved	Pyrimethamine decreases the activity of Multidrug and toxin extrusion protein 2 (SLC47A2).	[6]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Multidrug and toxin extrusion protein 2 (SLC47A2).	[4]
Verapamil	DMA7PEW	Phase 2/3 Trial	Verapamil decreases the activity of Multidrug and toxin extrusion protein 2 (SLC47A2).	[7]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Multidrug and toxin extrusion protein 2 (SLC47A2).	[2]

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] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [5] Cannabidiol enhances cytotoxicity of anti-cancer drugs in human head and neck squamous cell carcinoma. Sci Rep. 2020 Nov 26;10(1):20622. doi: 10.1038/s41598-020-77674-y.
• [6] Interactions between Oroxylin A with the solute carrier transporters and ATP-binding cassette transporters: Drug transporters profile for this flavonoid. Chem Biol Interact. 2020 Jun 1;324:109097. doi: 10.1016/j.cbi.2020.109097. Epub 2020 Apr 16.
• [7] Inhibition of organic anion transporter (OAT) activity by cigarette smoke condensate. Toxicol In Vitro. 2017 Oct;44:27-35.