Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTLRA7C0)

• DOT Name: Monocarboxylate transporter 8 (SLC16A2)
• Synonyms: MCT 8; Monocarboxylate transporter 7; MCT 7; Solute carrier family 16 member 2; X-linked PEST-containing transporter
• Gene Name: SLC16A2
• Related Disease: Allan-Herndon-Dudley syndrome
• UniProt ID: MOT8_HUMAN
• Pfam ID: PF07690
• Sequence:
  MALQSQASEEAKGPWQEADQEQQEPVGSPEPESEPEPEPEPEPVPVPPPEPQPEPQPLPD
  PAPLPELEFESERVHEPEPTPTVETRGTARGFQPPEGGFGWVVVFAATWCNGSIFGIHNS
  VGILYSMLLEEEKEKNRQVEFQAAWVGALAMGMIFFCSPIVSIFTDRLGCRITATAGAAV
  AFIGLHTSSFTSSLSLRYFTYGILFGCGCSFAFQPSLVILGHYFQRRLGLANGVVSAGSS
  IFSMSFPFLIRMLGDKIKLAQTFQVLSTFMFVLMLLSLTYRPLLPSSQDTPSKRGVRTLH
  QRFLAQLRKYFNMRVFRQRTYRIWAFGIAAAALGYFVPYVHLMKYVEEEFSEIKETWVLL
  VCIGATSGLGRLVSGHISDSIPGLKKIYLQVLSFLLLGLMSMMIPLCRDFGGLIVVCLFL
  GLCDGFFITIMAPIAFELVGPMQASQAIGYLLGMMALPMIAGPPIAGLLRNCFGDYHVAF
  YFAGVPPIIGAVILFFVPLMHQRMFKKEQRDSSKDKMLAPDPDPNGELLPGSPNPEEPI
• Function: Specific thyroid hormone transmembrane transporter, that mediates both uptake and efflux of thyroid hormones across the cell membrane independently of pH or a Na(+) gradient. Major substrates are the iodothyronines T3 and T4 and to a lesser extent rT3 and 3,3-diiodothyronine (3,3'-T2). Acts as an important mediator of thyroid hormone transport, especially T3, through the blood-brain barrier (Probable).
• Tissue Specificity: Highly expressed in liver and heart . In adult brain tissue expression is largely confined to endothelial cells of the blood-brain barrier (at protein level) .
• KEGG Pathway: Thyroid hormone sig.ling pathway (hsa04919)
• Reactome Pathway: Transport of organic anions (R-HSA-879518)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Allan-Herndon-Dudley syndrome	DIS7LD74	Definitive	X-linked	[1]

This DOT Affected the Regulation of Drug Effects of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Liothyronine	DM6IR3P	Approved	Monocarboxylate transporter 8 (SLC16A2) increases the uptake of Liothyronine.	[14]

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 Monocarboxylate transporter 8 (SLC16A2).	[2]

11 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 Monocarboxylate transporter 8 (SLC16A2).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Monocarboxylate transporter 8 (SLC16A2).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Monocarboxylate transporter 8 (SLC16A2).	[5]
Carbamazepine	DMZOLBI	Approved	Carbamazepine increases the expression of Monocarboxylate transporter 8 (SLC16A2).	[6]
Marinol	DM70IK5	Approved	Marinol increases the expression of Monocarboxylate transporter 8 (SLC16A2).	[7]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Monocarboxylate transporter 8 (SLC16A2).	[8]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of Monocarboxylate transporter 8 (SLC16A2).	[9]
DTI-015	DMXZRW0	Approved	DTI-015 increases the expression of Monocarboxylate transporter 8 (SLC16A2).	[10]
Zidovudine	DM4KI7O	Approved	Zidovudine increases the expression of Monocarboxylate transporter 8 (SLC16A2).	[11]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Monocarboxylate transporter 8 (SLC16A2).	[12]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Monocarboxylate transporter 8 (SLC16A2).	[13]

References

• [1] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [2] 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.
• [3] 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.
• [4] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [5] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [6] Transcriptional profiling of genes induced in the livers of patients treated with carbamazepine. Clin Pharmacol Ther. 2006 Nov;80(5):440-456.
• [7] 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.
• [8] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [9] Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
• [10] Gene expression profile induced by BCNU in human glioma cell lines with differential MGMT expression. J Neurooncol. 2005 Jul;73(3):189-98.
• [11] 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.
• [12] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [13] 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.
• [14] Application of a nonradioactive assay for high throughput screening for inhibition of thyroid hormone uptake via the transmembrane transporter MCT8. Toxicol In Vitro. 2017 Apr;40:234-242. doi: 10.1016/j.tiv.2017.01.014. Epub 2017 Jan 21.