Details of Drug Off-Target (DOT)

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

• DOT Name: Cationic amino acid transporter 2 (SLC7A2)
• Synonyms: CAT-2; CAT2; Low affinity cationic amino acid transporter 2; Solute carrier family 7 member 2
• Gene Name: SLC7A2
• UniProt ID: CTR2_HUMAN
• Pfam ID: PF13520 ; PF13906
• Sequence:
  MIPCRAALTFARCLIRRKIVTLDSLEDTKLCRCLSTMDLIALGVGSTLGAGVYVLAGEVA
  KADSGPSIVVSFLIAALASVMAGLCYAEFGARVPKTGSAYLYTYVTVGELWAFITGWNLI
  LSYVIGTSSVARAWSGTFDELLSKQIGQFLRTYFRMNYTGLAEYPDFFAVCLILLLAGLL
  SFGVKESAWVNKVFTAVNILVLLFVMVAGFVKGNVANWKISEEFLKNISASAREPPSENG
  TSIYGAGGFMPYGFTGTLAGAATCFYAFVGFDCIATTGEEVRNPQKAIPIGIVTSLLVCF
  MAYFGVSAALTLMMPYYLLDEKSPLPVAFEYVGWGPAKYVVAAGSLCALSTSLLGSIFPM
  PRVIYAMAEDGLLFKCLAQINSKTKTPIIATLSSGAVAALMAFLFDLKALVDMMSIGTLM
  AYSLVAACVLILRYQPGLSYDQPKCSPEKDGLGSSPRVTSKSESQVTMLQRQGFSMRTLF
  CPSLLPTQQSASLVSFLVGFLAFLVLGLSVLTTYGVHAITRLEAWSLALLALFLVLFVAI
  VLTIWRQPQNQQKVAFMVPFLPFLPAFSILVNIYLMVQLSADTWVRFSIWMAIGFLIYFS
  YGIRHSLEGHLRDENNEEDAYPDNVHAAAEEKSAIQANDHHPRNLSSPFIFHEKTSEF
• Function: Functions as a permease involved in the transport of the cationic amino acids (L-arginine, L-lysine, L-ornithine and L-homoarginine); the affinity for its substrates differs between isoforms created by alternative splicing. May play a role in classical or alternative activation of macrophages via its role in arginine transport; [Isoform 1]: Functions as a permease that mediates the transport of the cationic amino acids (L-arginine, L-lysine, L-ornithine and L-homoarginine). Shows a much higher affinity for L-arginine and L-homoarginine than isoform 2; [Isoform 2]: Functions as a low-affinity, high capacity permease involved in the transport of the cationic amino acids (L-arginine, L-lysine, L-ornithine and L-homoarginine).
• Tissue Specificity: Expressed at high levels in the skeletal muscle, placenta and ovary. Expressed at intermediate levels in the liver and pancreas and at low levels in the kidney and heart.
• Reactome Pathway: Amino acid transport across the plasma membrane (R-HSA-352230)

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
3-iodothyronamine	DM3L0F8	Investigative	Cationic amino acid transporter 2 (SLC7A2) affects the uptake of 3-iodothyronamine.	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Cationic amino acid transporter 2 (SLC7A2).	[1]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Cationic amino acid transporter 2 (SLC7A2).	[11]

16 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 Cationic amino acid transporter 2 (SLC7A2).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Cationic amino acid transporter 2 (SLC7A2).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen affects the expression of Cationic amino acid transporter 2 (SLC7A2).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Cationic amino acid transporter 2 (SLC7A2).	[5]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Cationic amino acid transporter 2 (SLC7A2).	[6]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Cationic amino acid transporter 2 (SLC7A2).	[7]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Cationic amino acid transporter 2 (SLC7A2).	[7]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of Cationic amino acid transporter 2 (SLC7A2).	[8]
Cytarabine	DMZD5QR	Approved	Cytarabine decreases the expression of Cationic amino acid transporter 2 (SLC7A2).	[9]
Zidovudine	DM4KI7O	Approved	Zidovudine decreases the expression of Cationic amino acid transporter 2 (SLC7A2).	[10]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Cationic amino acid transporter 2 (SLC7A2).	[12]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Cationic amino acid transporter 2 (SLC7A2).	[13]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Cationic amino acid transporter 2 (SLC7A2).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Cationic amino acid transporter 2 (SLC7A2).	[15]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Cationic amino acid transporter 2 (SLC7A2).	[16]
Nickel chloride	DMI12Y8	Investigative	Nickel chloride increases the expression of Cationic amino acid transporter 2 (SLC7A2).	[17]

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] Systems analysis of transcriptome and proteome in retinoic acid/arsenic trioxide-induced cell differentiation/apoptosis of promyelocytic leukemia. Proc Natl Acad Sci U S A. 2005 May 24;102(21):7653-8.
• [4] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [5] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [6] Persistent and non-persistent changes in gene expression result from long-term estrogen exposure of MCF-7 breast cancer cells. J Steroid Biochem Mol Biol. 2011 Feb;123(3-5):140-50.
• [7] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [8] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [9] 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.
• [10] 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.
• [11] 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.
• [12] BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell. 2011 Sep 16;146(6):904-17.
• [13] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [14] 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.
• [15] Bisphenolic compounds alter gene expression in MCF-7 cells through interaction with estrogen receptor . Toxicol Appl Pharmacol. 2020 Jul 15;399:115030. doi: 10.1016/j.taap.2020.115030. Epub 2020 May 6.
• [16] 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.
• [17] The contact allergen nickel triggers a unique inflammatory and proangiogenic gene expression pattern via activation of NF-kappaB and hypoxia-inducible factor-1alpha. J Immunol. 2007 Mar 1;178(5):3198-207.
• [18] Identification and characterization of 3-iodothyronamine intracellular transport. Endocrinology. 2009 Apr;150(4):1991-9.