Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTC36TYB)

• DOT Name: Organic cation/carnitine transporter 2 (SLC22A5)
• Synonyms: High-affinity sodium-dependent carnitine cotransporter; Solute carrier family 22 member 5
• Gene Name: SLC22A5
• Related Disease:
  Systemic primary carnitine deficiency disease
  Short QT syndrome
• UniProt ID: S22A5_HUMAN
• Pfam ID: PF00083
• Sequence:
  MRDYDEVTAFLGEWGPFQRLIFFLLSASIIPNGFTGLSSVFLIATPEHRCRVPDAANLSS
  AWRNHTVPLRLRDGREVPHSCRRYRLATIANFSALGLEPGRDVDLGQLEQESCLDGWEFS
  QDVYLSTIVTEWNLVCEDDWKAPLTISLFFVGVLLGSFISGQLSDRFGRKNVLFVTMGMQ
  TGFSFLQIFSKNFEMFVVLFVLVGMGQISNYVAAFVLGTEILGKSVRIIFSTLGVCIFYA
  FGYMVLPLFAYFIRDWRMLLVALTMPGVLCVALWWFIPESPRWLISQGRFEEAEVIIRKA
  AKANGIVVPSTIFDPSELQDLSSKKQQSHNILDLLRTWNIRMVTIMSIMLWMTISVGYFG
  LSLDTPNLHGDIFVNCFLSAMVEVPAYVLAWLLLQYLPRRYSMATALFLGGSVLLFMQLV
  PPDLYYLATVLVMVGKFGVTAAFSMVYVYTAELYPTVVRNMGVGVSSTASRLGSILSPYF
  VYLGAYDRFLPYILMGSLTILTAILTLFLPESFGTPLPDTIDQMLRVKGMKHRKTPSHTR
  MLKDGQERPTILKSTAF
• Function: Sodium-ion dependent, high affinity carnitine transporter. Involved in the active cellular uptake of carnitine. Transports one sodium ion with one molecule of carnitine. Also transports organic cations such as tetraethylammonium (TEA) without the involvement of sodium. Relative uptake activity ratio of carnitine to TEA is 11.3. In intestinal epithelia, transports the quorum-sensing pentapeptide CSF (competence and sporulation factor) from Bacillus Subtilis wich induces cytoprotective heat shock proteins contributing to intestinal homeostasis. May also contribute to regulate the transport of organic compounds in testis across the blood-testis-barrier (Probable); [Isoform 3]: Retained in the ER, unable to perform carnitine uptake.
• Tissue Specificity: Strongly expressed in kidney, skeletal muscle, heart and placenta . Primarily expressed by surface epithelial cells of the colon (at protein level) . Expressed in CD68 macrophage and CD43 T-cells but not in CD20 B-cells . In testis, localized to Sertoli cell basal membranes, peritubular myoid cells and Leydig cells .
• KEGG Pathway: Choline metabolism in cancer (hsa05231)
• Reactome Pathway:
  Organic cation transport (R-HSA-549127)
  Defective SLC22A5 causes systemic primary carnitine deficiency (CDSP) (R-HSA-5619053)
  Carnitine metabolism (R-HSA-200425)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Systemic primary carnitine deficiency disease	DIS9OPZ4	Definitive	Autosomal recessive	[1]
Short QT syndrome	DISOI9X1	Disputed	Autosomal recessive	[1]

This DOT Affected the Drug Response of 3 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Temozolomide	DMKECZD	Approved	Organic cation/carnitine transporter 2 (SLC22A5) affects the response to substance of Temozolomide.	[21]
Arsenic trioxide	DM61TA4	Approved	Organic cation/carnitine transporter 2 (SLC22A5) decreases the response to substance of Arsenic trioxide.	[22]
DTI-015	DMXZRW0	Approved	Organic cation/carnitine transporter 2 (SLC22A5) affects the response to substance of DTI-015.	[21]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Hydroxyurea	DMOQVU9	Approved	Organic cation/carnitine transporter 2 (SLC22A5) increases the uptake of Hydroxyurea.	[23]

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 Organic cation/carnitine transporter 2 (SLC22A5).	[2]
Arsenic	DMTL2Y1	Approved	Arsenic increases the methylation of Organic cation/carnitine transporter 2 (SLC22A5).	[8]

17 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 Organic cation/carnitine transporter 2 (SLC22A5).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Organic cation/carnitine transporter 2 (SLC22A5).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Organic cation/carnitine transporter 2 (SLC22A5).	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Organic cation/carnitine transporter 2 (SLC22A5).	[6]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Organic cation/carnitine transporter 2 (SLC22A5).	[7]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Organic cation/carnitine transporter 2 (SLC22A5).	[9]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Organic cation/carnitine transporter 2 (SLC22A5).	[10]
Carbamazepine	DMZOLBI	Approved	Carbamazepine decreases the expression of Organic cation/carnitine transporter 2 (SLC22A5).	[11]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of Organic cation/carnitine transporter 2 (SLC22A5).	[12]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Organic cation/carnitine transporter 2 (SLC22A5).	[13]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone increases the expression of Organic cation/carnitine transporter 2 (SLC22A5).	[14]
Zidovudine	DM4KI7O	Approved	Zidovudine increases the expression of Organic cation/carnitine transporter 2 (SLC22A5).	[15]
Levacecarnine HCL	DMJBOCR	Approved	Levacecarnine HCL decreases the expression of Organic cation/carnitine transporter 2 (SLC22A5).	[16]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Organic cation/carnitine transporter 2 (SLC22A5).	[17]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Organic cation/carnitine transporter 2 (SLC22A5).	[18]
Verapamil	DMA7PEW	Phase 2/3 Trial	Verapamil decreases the activity of Organic cation/carnitine transporter 2 (SLC22A5).	[19]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Organic cation/carnitine transporter 2 (SLC22A5).	[20]

References

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• [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] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [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] Urinary excretion of carnitine as a marker of proximal tubular damage associated with platin-based antineoplastic drugs. Nephrol Dial Transplant. 2010 Feb;25(2):426-33. doi: 10.1093/ndt/gfp456. Epub 2009 Sep 7.
• [7] Bisphenol-A and estradiol exert novel gene regulation in human MCF-7 derived breast cancer cells. Mol Cell Endocrinol. 2004 Jun 30;221(1-2):47-55. doi: 10.1016/j.mce.2004.04.010.
• [8] Inorganic arsenic as an endocrine disruptor: modulation of the glucocorticoid receptor pathway in placental cells via CpG methylation. Chem Res Toxicol. 2019 Mar 18;32(3):493-499.
• [9] 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.
• [10] 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.
• [11] Transcriptional profiling of genes induced in the livers of patients treated with carbamazepine. Clin Pharmacol Ther. 2006 Nov;80(5):440-456.
• [12] Multiple drug transporters mediate the placental transport of sulpiride. Arch Toxicol. 2017 Dec;91(12):3873-3884. doi: 10.1007/s00204-017-2008-8. Epub 2017 Jun 9.
• [13] Endometrial receptivity is affected in women with high circulating progesterone levels at the end of the follicular phase: a functional genomics analysis. Hum Reprod. 2011 Jul;26(7):1813-25.
• [14] Transcriptomic analysis of untreated and drug-treated differentiated HepaRG cells over a 2-week period. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):27-35.
• [15] 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.
• [16] Clozapine-induced reduction of l-carnitine reabsorption via inhibition/down-regulation of renal carnitine/organic cation transporter 2 contributes to liver lipid metabolic disorder in mice. Toxicol Appl Pharmacol. 2019 Jan 15;363:47-56. doi: 10.1016/j.taap.2018.11.007. Epub 2018 Nov 19.
• [17] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [18] 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.
• [19] Expression, localization, and function of the carnitine transporter octn2 (slc22a5) in human placenta. Drug Metab Dispos. 2005 Jan;33(1):31-7. doi: 10.1124/dmd.104.001560. Epub 2004 Oct 14.
• [20] 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.
• [21] Tumor necrosis factor-alpha-induced protein 3 as a putative regulator of nuclear factor-kappaB-mediated resistance to O6-alkylating agents in human glioblastomas. J Clin Oncol. 2006 Jan 10;24(2):274-87. doi: 10.1200/JCO.2005.02.9405. Epub 2005 Dec 19.
• [22] The NRF2-mediated oxidative stress response pathway is associated with tumor cell resistance to arsenic trioxide across the NCI-60 panel. BMC Med Genomics. 2010 Aug 13;3:37. doi: 10.1186/1755-8794-3-37.
• [23] Transcellular movement of hydroxyurea is mediated by specific solute carrier transporters. Exp Hematol. 2011 Apr;39(4):446-56.