Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT4LOVI9)

• DOT Name: Solute carrier family 22 member 4 (SLC22A4)
• Synonyms: Ergothioneine transporter; ET transporter; ETTh; Organic cation/carnitine transporter 1; OCTN1
• Gene Name: SLC22A4
• UniProt ID: S22A4_HUMAN
• Pfam ID: PF00083
• Sequence:
  MRDYDEVIAFLGEWGPFQRLIFFLLSASIIPNGFNGMSVVFLAGTPEHRCRVPDAANLSS
  AWRNNSVPLRLRDGREVPHSCSRYRLATIANFSALGLEPGRDVDLGQLEQESCLDGWEFS
  QDVYLSTVVTEWNLVCEDNWKVPLTTSLFFVGVLLGSFVSGQLSDRFGRKNVLFATMAVQ
  TGFSFLQIFSISWEMFTVLFVIVGMGQISNYVVAFILGTEILGKSVRIIFSTLGVCTFFA
  VGYMLLPLFAYFIRDWRMLLLALTVPGVLCVPLWWFIPESPRWLISQRRFREAEDIIQKA
  AKMNNIAVPAVIFDSVEELNPLKQQKAFILDLFRTRNIAIMTIMSLLLWMLTSVGYFALS
  LDAPNLHGDAYLNCFLSALIEIPAYITAWLLLRTLPRRYIIAAVLFWGGGVLLFIQLVPV
  DYYFLSIGLVMLGKFGITSAFSMLYVFTAELYPTLVRNMAVGVTSTASRVGSIIAPYFVY
  LGAYNRMLPYIVMGSLTVLIGILTLFFPESLGMTLPETLEQMQKVKWFRSGKKTRDSMET
  EENPKVLITAF
• Function: Transporter that mediates the transport of endogenous and microbial zwitterions and organic cations. Functions as a Na(+)-dependent and pH-dependent high affinity microbial symporter of potent food-derived antioxidant ergothioeine. Transports one sodium ion with one ergothioeine molecule. Involved in the absorption of ergothioneine from the luminal/apical side of the small intestine and renal tubular cells, and into non-parenchymal liver cells, thereby contributing to maintain steady-state ergothioneine level in the body. Also mediates the bidirectional transport of acetycholine, although the exact transport mechanism has not been fully identified yet. Most likely exports anti-inflammatory acetylcholine in non-neuronal tissues, thereby contributing to the non-neuronal cholinergic system. Displays a general physiological role linked to better survival by controlling inflammation and oxidative stress, which may be related to ergothioneine and acetycholine transports. May also function as a low-affinity Na(+)-dependent transporter of L-carnitine through the mitochondrial membrane, thereby maintaining intracellular carnitine homeostasis. May contribute to regulate the transport of cationic compounds in testis across the blood-testis-barrier.
• Tissue Specificity: Widely expressed . Highly expressed in kidney, trachea, ileum, bone marrow and whole blood . Expressed in small intestines . Weakly expressed in skeletal muscle, prostate, lung, pancreas, placenta, heart, uterus, spleen and spinal cord . Expressed in testis, primarily to the basal membrane of Sertoli cells . Expressed in brain . Expressed in liver . Highly expressed in intestinal cell types affected by Crohn disease, including epithelial cells. Expressed in CD68 macrophage and CD43 T-cells but not in CD20 B-cells . Predominantly expressed in CD14 cells in peripheral blood mononuclear cells . Expressed in fetal liver, kidney and lung .
• KEGG Pathway: Choline metabolism in cancer (hsa05231)
• Reactome Pathway: Organic cation transport (R-HSA-549127)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Regulation of Drug Effects of 3 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Hydroxyurea	DMOQVU9	Approved	Solute carrier family 22 member 4 (SLC22A4) increases the uptake of Hydroxyurea.	[18]
Levacecarnine HCL	DMJBOCR	Approved	Solute carrier family 22 member 4 (SLC22A4) increases the uptake of Levacecarnine HCL.	[18]
[14C]TEA	DM6SFYH	Investigative	Solute carrier family 22 member 4 (SLC22A4) increases the transport of [14C]TEA.	[17]

18 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 22 member 4 (SLC22A4).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Solute carrier family 22 member 4 (SLC22A4).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Solute carrier family 22 member 4 (SLC22A4).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Solute carrier family 22 member 4 (SLC22A4).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Solute carrier family 22 member 4 (SLC22A4).	[5]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Solute carrier family 22 member 4 (SLC22A4).	[6]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of Solute carrier family 22 member 4 (SLC22A4).	[7]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Solute carrier family 22 member 4 (SLC22A4).	[8]
Troglitazone	DM3VFPD	Approved	Troglitazone increases the expression of Solute carrier family 22 member 4 (SLC22A4).	[9]
Sodium lauryl sulfate	DMLJ634	Approved	Sodium lauryl sulfate increases the expression of Solute carrier family 22 member 4 (SLC22A4).	[10]
Zidovudine	DM4KI7O	Approved	Zidovudine increases the expression of Solute carrier family 22 member 4 (SLC22A4).	[11]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Solute carrier family 22 member 4 (SLC22A4).	[2]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Solute carrier family 22 member 4 (SLC22A4).	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Solute carrier family 22 member 4 (SLC22A4).	[13]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Solute carrier family 22 member 4 (SLC22A4).	[14]
CH-223191	DMMJZYC	Investigative	CH-223191 decreases the expression of Solute carrier family 22 member 4 (SLC22A4).	[15]
Cycloheximide	DMGDA3C	Investigative	Cycloheximide increases the expression of Solute carrier family 22 member 4 (SLC22A4).	[16]
MTSEA	DM8KPWM	Investigative	MTSEA decreases the activity of Solute carrier family 22 member 4 (SLC22A4).	[17]

References

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• [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] Retinoic acid receptor alpha amplifications and retinoic acid sensitivity in breast cancers. Clin Breast Cancer. 2013 Oct;13(5):401-8.
• [4] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [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] Long-term estrogen exposure promotes carcinogen bioactivation, induces persistent changes in gene expression, and enhances the tumorigenicity of MCF-7 human breast cancer cells. Toxicol Appl Pharmacol. 2009 Nov 1;240(3):355-66.
• [7] 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.
• [8] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [9] Effects of ciglitazone and troglitazone on the proliferation of human stomach cancer cells. World J Gastroenterol. 2009 Jan 21;15(3):310-20.
• [10] CXCL14 downregulation in human keratinocytes is a potential biomarker for a novel in vitro skin sensitization test. Toxicol Appl Pharmacol. 2020 Jan 1;386:114828. doi: 10.1016/j.taap.2019.114828. Epub 2019 Nov 14.
• [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] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [13] Comparison of transcriptome expression alterations by chronic exposure to low-dose bisphenol A in different subtypes of breast cancer cells. Toxicol Appl Pharmacol. 2019 Dec 15;385:114814. doi: 10.1016/j.taap.2019.114814. Epub 2019 Nov 9.
• [14] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [15] The Ah receptor regulates growth factor expression in head and neck squamous cell carcinoma cell lines. Mol Carcinog. 2014 Oct;53(10):765-76.
• [16] Comparative analysis of AhR-mediated TCDD-elicited gene expression in human liver adult stem cells. Toxicol Sci. 2009 Nov;112(1):229-44.
• [17] Functional and molecular effects of mercury compounds on the human OCTN1 cation transporter: C50 and C136 are the targets for potent inhibition. Toxicol Sci. 2015 Mar;144(1):105-13. doi: 10.1093/toxsci/kfu259. Epub 2014 Dec 8.
• [18] Transcellular movement of hydroxyurea is mediated by specific solute carrier transporters. Exp Hematol. 2011 Apr;39(4):446-56.