Details of Drug Off-Target (DOT)

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

• DOT Name: Monocarboxylate transporter 4 (SLC16A3)
• Synonyms: MCT 4; Solute carrier family 16 member 3
• Gene Name: SLC16A3
• UniProt ID: MOT4_HUMAN
• Pfam ID: PF07690
• Sequence:
  MGGAVVDEGPTGVKAPDGGWGWAVLFGCFVITGFSYAFPKAVSVFFKELIQEFGIGYSDT
  AWISSILLAMLYGTGPLCSVCVNRFGCRPVMLVGGLFASLGMVAASFCRSIIQVYLTTGV
  ITGLGLALNFQPSLIMLNRYFSKRRPMANGLAAAGSPVFLCALSPLGQLLQDRYGWRGGF
  LILGGLLLNCCVCAALMRPLVVTAQPGSGPPRPSRRLLDLSVFRDRGFVLYAVAASVMVL
  GLFVPPVFVVSYAKDLGVPDTKAAFLLTILGFIDIFARPAAGFVAGLGKVRPYSVYLFSF
  SMFFNGLADLAGSTAGDYGGLVVFCIFFGISYGMVGALQFEVLMAIVGTHKFSSAIGLVL
  LMEAVAVLVGPPSGGKLLDATHVYMYVFILAGAEVLTSSLILLLGNFFCIRKKPKEPQPE
  VAAAEEEKLHKPPADSGVDLREVEHFLKAEPEKNGEVVHTPETSV
• Function: Proton-dependent transporter of monocarboxylates such as L-lactate and pyruvate. Plays a predominant role in L-lactate efflux from highly glycolytic cells.
• Tissue Specificity: Highly expressed in skeletal muscle.
• KEGG Pathway: Central carbon metabolism in cancer (hsa05230)
• Reactome Pathway:
  Proton-coupled monocarboxylate transport (R-HSA-433692)
  Pyruvate metabolism (R-HSA-70268)
  Basigin interactions (R-HSA-210991)

Molecular Interaction Atlas (MIA) of This DOT

4 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 Monocarboxylate transporter 4 (SLC16A3).	[1]
Arsenic	DMTL2Y1	Approved	Arsenic increases the ubiquitination of Monocarboxylate transporter 4 (SLC16A3).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Monocarboxylate transporter 4 (SLC16A3).	[20]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Monocarboxylate transporter 4 (SLC16A3).	[22]

24 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Monocarboxylate transporter 4 (SLC16A3).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Monocarboxylate transporter 4 (SLC16A3).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Monocarboxylate transporter 4 (SLC16A3).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin affects the expression of Monocarboxylate transporter 4 (SLC16A3).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Monocarboxylate transporter 4 (SLC16A3).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin affects the expression of Monocarboxylate transporter 4 (SLC16A3).	[7]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Monocarboxylate transporter 4 (SLC16A3).	[8]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Monocarboxylate transporter 4 (SLC16A3).	[9]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Monocarboxylate transporter 4 (SLC16A3).	[8]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Monocarboxylate transporter 4 (SLC16A3).	[11]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Monocarboxylate transporter 4 (SLC16A3).	[12]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of Monocarboxylate transporter 4 (SLC16A3).	[13]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Monocarboxylate transporter 4 (SLC16A3).	[14]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Monocarboxylate transporter 4 (SLC16A3).	[12]
Cytarabine	DMZD5QR	Approved	Cytarabine decreases the expression of Monocarboxylate transporter 4 (SLC16A3).	[15]
Zidovudine	DM4KI7O	Approved	Zidovudine decreases the expression of Monocarboxylate transporter 4 (SLC16A3).	[16]
Liothyronine	DM6IR3P	Approved	Liothyronine increases the expression of Monocarboxylate transporter 4 (SLC16A3).	[17]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Monocarboxylate transporter 4 (SLC16A3).	[18]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene increases the expression of Monocarboxylate transporter 4 (SLC16A3).	[3]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Monocarboxylate transporter 4 (SLC16A3).	[19]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Monocarboxylate transporter 4 (SLC16A3).	[19]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Monocarboxylate transporter 4 (SLC16A3).	[21]
chloropicrin	DMSGBQA	Investigative	chloropicrin decreases the expression of Monocarboxylate transporter 4 (SLC16A3).	[23]
Manganese	DMKT129	Investigative	Manganese increases the expression of Monocarboxylate transporter 4 (SLC16A3).	[24]

References

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• [4] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
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• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [8] 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.
• [9] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [10] Quantitative Assessment of Arsenite-Induced Perturbation of Ubiquitinated Proteome. Chem Res Toxicol. 2022 Sep 19;35(9):1589-1597. doi: 10.1021/acs.chemrestox.2c00197. Epub 2022 Aug 22.
• [11] 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.
• [12] 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.
• [13] The DNA methyltransferase inhibitors azacitidine, decitabine and zebularine exert differential effects on cancer gene expression in acute myeloid leukemia cells. Leukemia. 2009 Jun;23(6):1019-28.
• [14] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [15] 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.
• [16] 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.
• [17] Thyroid hormone responsive genes in cultured human fibroblasts. J Clin Endocrinol Metab. 2005 Feb;90(2):936-43.
• [18] 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.
• [19] 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.
• [20] 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.
• [21] 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.
• [22] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [23] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.
• [24] Gene expression profiling of human primary astrocytes exposed to manganese chloride indicates selective effects on several functions of the cells. Neurotoxicology. 2007 May;28(3):478-89.