Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTW1UTZ7)

• DOT Name: Monocarboxylate transporter 1 (SLC16A1)
• Synonyms: MCT 1; Solute carrier family 16 member 1
• Gene Name: SLC16A1
• Related Disease:
  Ketoacidosis due to monocarboxylate transporter-1 deficiency
  Exercise-induced hyperinsulinism
  Metabolic myopathy due to lactate transporter defect
• UniProt ID: MOT1_HUMAN
• PDB ID: 6LYY; 6LZ0; 7CKO; 7CKR; 7DA5; 7YR5
• Pfam ID: PF07690
• Sequence:
  MPPAVGGPVGYTPPDGGWGWAVVIGAFISIGFSYAFPKSITVFFKEIEGIFHATTSEVSW
  ISSIMLAVMYGGGPISSILVNKYGSRIVMIVGGCLSGCGLIAASFCNTVQQLYVCIGVIG
  GLGLAFNLNPALTMIGKYFYKRRPLANGLAMAGSPVFLCTLAPLNQVFFGIFGWRGSFLI
  LGGLLLNCCVAGALMRPIGPKPTKAGKDKSKASLEKAGKSGVKKDLHDANTDLIGRHPKQ
  EKRSVFQTINQFLDLTLFTHRGFLLYLSGNVIMFFGLFAPLVFLSSYGKSQHYSSEKSAF
  LLSILAFVDMVARPSMGLVANTKPIRPRIQYFFAASVVANGVCHMLAPLSTTYVGFCVYA
  GFFGFAFGWLSSVLFETLMDLVGPQRFSSAVGLVTIVECCPVLLGPPLLGRLNDMYGDYK
  YTYWACGVVLIISGIYLFIGMGINYRLLAKEQKANEQKKESKEEETSIDVAGKPNEVTKA
  AESPDQKDTDGGPKEEESPV
• Function: Bidirectional proton-coupled monocarboxylate transporter. Catalyzes the rapid transport across the plasma membrane of many monocarboxylates such as lactate, pyruvate, acetate and the ketone bodies acetoacetate and beta-hydroxybutyrate, and thus contributes to the maintenance of intracellular pH. The transport direction is determined by the proton motive force and the concentration gradient of the substrate monocarboxylate. MCT1 is a major lactate exporter. Plays a role in cellular responses to a high-fat diet by modulating the cellular levels of lactate and pyruvate that contribute to the regulation of central metabolic pathways and insulin secretion, with concomitant effects on plasma insulin levels and blood glucose homeostasis. Facilitates the protonated monocarboxylate form of succinate export, that its transient protonation upon muscle cell acidification in exercising muscle and ischemic heart. Functions via alternate outward- and inward-open conformation states. Protonation and deprotonation of 309-Asp is essential for the conformational transition.
• Tissue Specificity: Widely expressed . Detected in heart and in blood lymphocytes and monocytes (at protein level) .
• KEGG Pathway: Efferocytosis (hsa04148)
• Reactome Pathway:
  Proton-coupled monocarboxylate transport (R-HSA-433692)
  Defective SLC16A1 causes symptomatic deficiency in lactate transport (SDLT) (R-HSA-5619070)
  Pyruvate metabolism (R-HSA-70268)
  Aspirin ADME (R-HSA-9749641)
  Basigin interactions (R-HSA-210991)
• BioCyc Pathway: MetaCyc:ENSG00000155380-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Ketoacidosis due to monocarboxylate transporter-1 deficiency	DISL8IQR	Strong	Autosomal recessive	[1]
Exercise-induced hyperinsulinism	DISSTKBS	Supportive	Autosomal dominant	[2]
Metabolic myopathy due to lactate transporter defect	DISWIOHL	Limited	Unknown	[3]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Josamycin	DMKJ8LB	Approved	Monocarboxylate transporter 1 (SLC16A1) affects the response to substance of Josamycin.	[30]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzoic acid	DMKB9FI	Approved	Monocarboxylate transporter 1 (SLC16A1) increases the uptake of Benzoic acid.	[31]
Milchsaure	DM462BT	Investigative	Monocarboxylate transporter 1 (SLC16A1) increases the uptake of Milchsaure.	[32]

32 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 Monocarboxylate transporter 1 (SLC16A1).	[4]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Monocarboxylate transporter 1 (SLC16A1).	[5]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Monocarboxylate transporter 1 (SLC16A1).	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Monocarboxylate transporter 1 (SLC16A1).	[7]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Monocarboxylate transporter 1 (SLC16A1).	[8]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Monocarboxylate transporter 1 (SLC16A1).	[9]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Monocarboxylate transporter 1 (SLC16A1).	[10]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Monocarboxylate transporter 1 (SLC16A1).	[11]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of Monocarboxylate transporter 1 (SLC16A1).	[12]
Marinol	DM70IK5	Approved	Marinol increases the expression of Monocarboxylate transporter 1 (SLC16A1).	[13]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Monocarboxylate transporter 1 (SLC16A1).	[14]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil decreases the expression of Monocarboxylate transporter 1 (SLC16A1).	[15]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Monocarboxylate transporter 1 (SLC16A1).	[16]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Monocarboxylate transporter 1 (SLC16A1).	[17]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Monocarboxylate transporter 1 (SLC16A1).	[6]
Aspirin	DM672AH	Approved	Aspirin decreases the expression of Monocarboxylate transporter 1 (SLC16A1).	[18]
Piroxicam	DMTK234	Approved	Piroxicam increases the expression of Monocarboxylate transporter 1 (SLC16A1).	[19]
Indomethacin	DMSC4A7	Approved	Indomethacin decreases the expression of Monocarboxylate transporter 1 (SLC16A1).	[20]
Zidovudine	DM4KI7O	Approved	Zidovudine decreases the expression of Monocarboxylate transporter 1 (SLC16A1).	[21]
Alitretinoin	DMME8LH	Approved	Alitretinoin decreases the expression of Monocarboxylate transporter 1 (SLC16A1).	[6]
Acetic Acid, Glacial	DM4SJ5Y	Approved	Acetic Acid, Glacial increases the expression of Monocarboxylate transporter 1 (SLC16A1).	[22]
Motexafin gadolinium	DMEJKRF	Approved	Motexafin gadolinium increases the expression of Monocarboxylate transporter 1 (SLC16A1).	[22]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Monocarboxylate transporter 1 (SLC16A1).	[16]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene affects the expression of Monocarboxylate transporter 1 (SLC16A1).	[23]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Monocarboxylate transporter 1 (SLC16A1).	[24]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Monocarboxylate transporter 1 (SLC16A1).	[26]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the expression of Monocarboxylate transporter 1 (SLC16A1).	[13]
Geldanamycin	DMS7TC5	Discontinued in Phase 2	Geldanamycin increases the expression of Monocarboxylate transporter 1 (SLC16A1).	[27]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Monocarboxylate transporter 1 (SLC16A1).	[12]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Monocarboxylate transporter 1 (SLC16A1).	[29]
all-trans-4-oxo-retinoic acid	DMM2R1N	Investigative	all-trans-4-oxo-retinoic acid decreases the expression of Monocarboxylate transporter 1 (SLC16A1).	[6]
Methylenedioxymethamphetamine	DMYVU47	Investigative	Methylenedioxymethamphetamine increases the expression of Monocarboxylate transporter 1 (SLC16A1).	[13]

2 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 affects the methylation of Monocarboxylate transporter 1 (SLC16A1).	[25]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Monocarboxylate transporter 1 (SLC16A1).	[28]

References

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• [3] Mutations in MCT1 cDNA in patients with symptomatic deficiency in lactate transport. Muscle Nerve. 2000 Jan;23(1):90-7. doi: 10.1002/(sici)1097-4598(200001)23:1<90::aid-mus12>3.0.co;2-m.
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• [17] The effect of folate status on the uptake of physiologically relevant compounds by Caco-2 cells. Eur J Pharmacol. 2010 Aug 25;640(1-3):29-37. doi: 10.1016/j.ejphar.2010.04.056. Epub 2010 May 11.
• [18] Expression profile analysis of colon cancer cells in response to sulindac or aspirin. Biochem Biophys Res Commun. 2002 Mar 29;292(2):498-512.
• [19] Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
• [20] Mechanisms of indomethacin-induced alterations in the choline phospholipid metabolism of breast cancer cells. Neoplasia. 2006 Sep;8(9):758-71.
• [21] 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.
• [22] Motexafin gadolinium and zinc induce oxidative stress responses and apoptosis in B-cell lymphoma lines. Cancer Res. 2005 Dec 15;65(24):11676-88.
• [23] Differential modulation of PI3-kinase/Akt pathway during all-trans retinoic acid- and Am80-induced HL-60 cell differentiation revealed by DNA microarray analysis. Biochem Pharmacol. 2004 Dec 1;68(11):2177-86.
• [24] Dose- and time-dependent transcriptional response of Ishikawa cells exposed to genistein. Toxicol Sci. 2016 May;151(1):71-87.
• [25] 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.
• [26] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
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• [28] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
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• [30] A genome-wide analysis of targets of macrolide antibiotics in mammalian cells. J Biol Chem. 2020 Feb 14;295(7):2057-2067. doi: 10.1074/jbc.RA119.010770. Epub 2020 Jan 8.
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• [32] Functional activity of a monocarboxylate transporter, MCT1, in the human retinal pigmented epithelium cell line, ARPE-19. Mol Pharm. 2005 Mar-Apr;2(2):109-17. doi: 10.1021/mp0499050.