Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTXL3KAM)

• DOT Name: Solute carrier family 49 member 4 (SLC49A4)
• Synonyms: Disrupted in renal cancer protein 2; Disrupted in renal carcinoma protein 2
• Gene Name: SLC49A4
• Related Disease:
  Clear cell renal carcinoma
  Carcinoma
  Neoplasm
  Renal carcinoma
  Von hippel-lindau disease
  Renal cell carcinoma
• UniProt ID: DIRC2_HUMAN
• Pfam ID: PF07690
• Sequence:
  MGSRWSSEEERQPLLGPGLGPGLGASWRSREAAAAALPAAVPGPGRVYGRRWLVLLLFSL
  LAFVQGLVWNTWGPIQNSARQAYGFSSWDIALLVLWGPIGFLPCFAFMWLLDKRGLRITV
  LLTSFLMVLGTGLRCIPISDLILKRRLIHGGQMLNGLAGPTVMNAAPFLSTTWFSADERA
  TATAIASMLSYLGGACAFLVGPLVVPAPNGTSPLLAAESSRAHIKDRIEAVLYAEFGVVC
  LIFSATLAYFPPRPPLPPSVAAASQRLSYRRSVCRLLSNFRFLMIALAYAIPLGVFAGWS
  GVLDLILTPAHVSQVDAGWIGFWSIVGGCVVGIAMARFADFIRGMLKLILLLLFSGATLS
  STWFTLTCLNSITHLPLTTVTLYASCILLGVFLNSSVPIFFELFVETVYPVPEGITCGVV
  TFLSNMFMGVLLFFLTFYHTELSWFNWCLPGSCLLSLLLILCFRESYDRLYLDVVVSV
• Function: Mediates H(+)-dependent pyridoxine transport.
• Tissue Specificity: Ubiquitous. Expressed in proximal tubular cells of the kidney. Highly expressed in the placenta, brain and heart.

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Clear cell renal carcinoma	DISBXRFJ	Definitive	Biomarker	[1]
Carcinoma	DISH9F1N	Strong	Biomarker	[2]
Neoplasm	DISZKGEW	Strong	Biomarker	[3]
Renal carcinoma	DISER9XT	Strong	Biomarker	[4]
Von hippel-lindau disease	DIS6ZFQQ	Strong	Biomarker	[3]
Renal cell carcinoma	DISQZ2X8	moderate	Biomarker	[5]

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 Solute carrier family 49 member 4 (SLC49A4).	[6]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Solute carrier family 49 member 4 (SLC49A4).	[7]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Solute carrier family 49 member 4 (SLC49A4).	[8]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Solute carrier family 49 member 4 (SLC49A4).	[9]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Solute carrier family 49 member 4 (SLC49A4).	[10]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Solute carrier family 49 member 4 (SLC49A4).	[12]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Solute carrier family 49 member 4 (SLC49A4).	[13]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Solute carrier family 49 member 4 (SLC49A4).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Solute carrier family 49 member 4 (SLC49A4).	[15]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Solute carrier family 49 member 4 (SLC49A4).	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic increases the methylation of Solute carrier family 49 member 4 (SLC49A4).	[11]

References

• [1] Mutant versions of von Hippel-Lindau (VHL) can protect HIF1 from SART1-mediated degradation in clear-cell renal cell carcinoma.Oncogene. 2016 Feb 4;35(5):587-94. doi: 10.1038/onc.2015.113. Epub 2015 Apr 27.
• [2] Heme and FLVCR-related transporter families SLC48 and SLC49. Mol Aspects Med. 2013 Apr-Jun;34(2-3):669-82.
• [3] Discovery of a novel 2,5-dihydroxycinnamic acid-based 5-lipoxygenase inhibitor that induces apoptosis and may impair autophagic flux in RCC4 renal cancer cells.Eur J Med Chem. 2019 Oct 1;179:347-357. doi: 10.1016/j.ejmech.2019.06.060. Epub 2019 Jun 23.
• [4] p300 relieves p53-evoked transcriptional repression of hypoxia-inducible factor-1 (HIF-1).Biochem J. 2004 May 15;380(Pt 1):289-95. doi: 10.1042/BJ20031299.
• [5] Different Cytokine and Chemokine Expression Patterns in Malignant Compared to Those in Nonmalignant Renal Cells.Anal Cell Pathol (Amst). 2017;2017:7190546. doi: 10.1155/2017/7190546. Epub 2017 Jul 9.
• [6] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [7] 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.
• [8] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [9] 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.
• [10] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [11] Epigenetic changes in individuals with arsenicosis. Chem Res Toxicol. 2011 Feb 18;24(2):165-7. doi: 10.1021/tx1004419. Epub 2011 Feb 4.
• [12] 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.
• [13] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [14] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [15] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [16] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.