Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT3J1G7H)

• DOT Name: Solute carrier organic anion transporter family member 4A1 (SLCO4A1)
• Synonyms: OATP4A1; Colon organic anion transporter; Organic anion transporter polypeptide-related protein 1; OATP-RP1; OATPRP1; POAT; Organic anion-transporting polypeptide E; OATP-E; Sodium-independent organic anion transporter E; Solute carrier family 21 member 12
• Gene Name: SLCO4A1
• UniProt ID: SO4A1_HUMAN
• Pfam ID: PF07648 ; PF03137
• Sequence:
  MPLHQLGDKPLTFPSPNSAMENGLDHTPPSRRASPGTPLSPGSLRSAAHSPLDTSKQPLC
  QLWAEKHGARGTHEVRYVSAGQSVACGWWAFAPPCLQVLNTPKGILFFLCAAAFLQGMTV
  NGFINTVITSLERRYDLHSYQSGLIASSYDIAACLCLTFVSYFGGSGHKPRWLGWGVLLM
  GTGSLVFALPHFTAGRYEVELDAGVRTCPANPGAVCADSTSGLSRYQLVFMLGQFLHGVG
  ATPLYTLGVTYLDENVKSSCSPVYIAIFYTAAILGPAAGYLIGGALLNIYTEMGRRTELT
  TESPLWVGAWWVGFLGSGAAAFFTAVPILGYPRQLPGSQRYAVMRAAEMHQLKDSSRGEA
  SNPDFGKTIRDLPLSIWLLLKNPTFILLCLAGATEATLITGMSTFSPKFLESQFSLSASE
  AATLFGYLVVPAGGGGTFLGGFFVNKLRLRGSAVIKFCLFCTVVSLLGILVFSLHCPSVP
  MAGVTASYGGSLLPEGHLNLTAPCNAACSCQPEHYSPVCGSDGLMYFSLCHAGCPAATET
  NVDGQKVYRDCSCIPQNLSSGFGHATAGKCTSTCQRKPLLLVFIFVVIFFTFLSSIPALT
  ATLRCVRDPQRSFALGIQWIVVRILGGIPGPIAFGWVIDKACLLWQDQCGQQGSCLVYQN
  SAMSRYILIMGLLYKVLGVLFFAIACFLYKPLSESSDGLETCLPSQSSAPDSATDSQLQS
  SV
• Function: Organic anion antiporter with apparent broad substrate specificity. Recognizes various substrates including thyroid hormones 3,3',5-triiodo-L-thyronine (T3), L-thyroxine (T4) and 3,3',5'-triiodo-L-thyronine (rT3), conjugated steroids such as estrone 3-sulfate and estradiol 17-beta glucuronide, bile acids such as taurocholate and prostanoids such as prostaglandin E2, likely operating in a tissue-specific manner. May be involved in uptake of metabolites from the circulation into organs such as kidney, liver or placenta. Possibly drives the selective transport of thyroid hormones and estrogens coupled to an outward glutamate gradient across the microvillous membrane of the placenta. The transport mechanism, its electrogenicity and potential tissue-specific counterions remain to be elucidated (Probable).
• Tissue Specificity: Widely expressed . Expressed in placental trophoblasts . Expressed in pancreas, kidney, skeletal muscle, liver, lung, brain, heart, colon, small intestine, ovary, testis, prostate, thymus and spleen. In testis, primarily localized to Leydig cells .
• Reactome Pathway: Transport of organic anions (R-HSA-879518)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Mitoxantrone	DMM39BF	Approved	Solute carrier organic anion transporter family member 4A1 (SLCO4A1) affects the response to substance of Mitoxantrone.	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
3-iodothyronamine	DM3L0F8	Investigative	Solute carrier organic anion transporter family member 4A1 (SLCO4A1) affects the uptake of 3-iodothyronamine.	[20]

5 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 Solute carrier organic anion transporter family member 4A1 (SLCO4A1).	[1]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Solute carrier organic anion transporter family member 4A1 (SLCO4A1).	[12]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Solute carrier organic anion transporter family member 4A1 (SLCO4A1).	[13]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Solute carrier organic anion transporter family member 4A1 (SLCO4A1).	[14]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Solute carrier organic anion transporter family member 4A1 (SLCO4A1).	[13]

15 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 Solute carrier organic anion transporter family member 4A1 (SLCO4A1).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Solute carrier organic anion transporter family member 4A1 (SLCO4A1).	[3]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Solute carrier organic anion transporter family member 4A1 (SLCO4A1).	[4]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Solute carrier organic anion transporter family member 4A1 (SLCO4A1).	[5]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Solute carrier organic anion transporter family member 4A1 (SLCO4A1).	[6]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Solute carrier organic anion transporter family member 4A1 (SLCO4A1).	[7]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Solute carrier organic anion transporter family member 4A1 (SLCO4A1).	[8]
Malathion	DMXZ84M	Approved	Malathion increases the expression of Solute carrier organic anion transporter family member 4A1 (SLCO4A1).	[9]
Zidovudine	DM4KI7O	Approved	Zidovudine decreases the expression of Solute carrier organic anion transporter family member 4A1 (SLCO4A1).	[10]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Solute carrier organic anion transporter family member 4A1 (SLCO4A1).	[11]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Solute carrier organic anion transporter family member 4A1 (SLCO4A1).	[15]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Solute carrier organic anion transporter family member 4A1 (SLCO4A1).	[16]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Solute carrier organic anion transporter family member 4A1 (SLCO4A1).	[17]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of Solute carrier organic anion transporter family member 4A1 (SLCO4A1).	[18]
OXYQUINOLINE	DMZVS9Y	Investigative	OXYQUINOLINE increases the expression of Solute carrier organic anion transporter family member 4A1 (SLCO4A1).	[7]

References

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• [2] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [3] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [4] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [5] Comparative Analysis of Transcriptomic Changes including mRNA and microRNA Expression Induced by the Xenoestrogens Zearalenone and Bisphenol A in Human Ovarian Cells. Toxins (Basel). 2023 Feb 9;15(2):140. doi: 10.3390/toxins15020140.
• [6] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [7] 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.
• [8] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [9] Exposure to Insecticides Modifies Gene Expression and DNA Methylation in Hematopoietic Tissues In Vitro. Int J Mol Sci. 2023 Mar 26;24(7):6259. doi: 10.3390/ijms24076259.
• [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] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [12] 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.
• [13] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [14] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [15] 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.
• [16] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [17] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [18] Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.
• [19] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.
• [20] Identification and characterization of 3-iodothyronamine intracellular transport. Endocrinology. 2009 Apr;150(4):1991-9.