Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTO4BJCC)

• DOT Name: Organic anion transporter 7 (SLC22A9)
• Synonyms: OAT7; Organic anion/short-chain fatty acid exchanger; Solute carrier family 22 member 9
• Gene Name: SLC22A9
• UniProt ID: S22A9_HUMAN
• Pfam ID: PF07690
• Sequence:
  MAFQDLLGHAGDLWRFQILQTVFLSIFAVATYLHFMLENFTAFIPGHRCWVHILDNDTVS
  DNDTGALSQDALLRISIPLDSNMRPEKCRRFVHPQWQLLHLNGTFPNTSDADMEPCVDGW
  VYDRISFSSTIVTEWDLVCDSQSLTSVAKFVFMAGMMVGGILGGHLSDRFGRRFVLRWCY
  LQVAIVGTCAALAPTFLIYCSLRFLSGIAAMSLITNTIMLIAEWATHRFQAMGITLGMCP
  SGIAFMTLAGLAFAIRDWHILQLVVSVPYFVIFLTSSWLLESARWLIINNKPEEGLKELR
  KAAHRSGMKNARDTLTLEILKSTMKKELEAAQKKKPSLCEMLHMPNICKRISLLSFTRFA
  NFMAYFGLNLHVQHLGNNVFLLQTLFGAVILLANCVAPWALKYMNRRASQMLLMFLLAIC
  LLAIIFVPQEMQTLREVLATLGLGASALANTLAFAHGNEVIPTIIRARAMGINATFANIA
  GALAPLMMILSVYSPPLPWIIYGVFPFISGFAFLLLPETRNKPLFDTIQDEKNERKDPRE
  PKQEDPRVEVTQF
• Function: Sodium-independent organic anion transporter, exhibits high specificity for sulfated conjugates of xenobiotics and steroid hormones such as estrone 3-sulfate (E1S) and dehydroepiandrosterone sulfate (DHEAS). Can transport the statin pravastatin and may contribute to its disposition into the hepatocytes when the function of OATPs is compromised. It is specifically activated by 3 to 5 carbons-containing short-chain fatty acids/SCFAs, including propionate (propanoate), butyrate (butanoate) and valerate (pentanoate). May operate the exchange of sulfated organic components against short-chain fatty acids/SCFAs, in particular butanoate, at the sinusoidal membrane of hepatocytes.
• Tissue Specificity: Specifically expressed in liver (also at protein level).

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Regulation of Drug Effects of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Tetracycline	DMZA017	Approved	Organic anion transporter 7 (SLC22A9) increases the export of Tetracycline.	[15]
[3H]estrone-3-sulphate	DMGPF0N	Investigative	Organic anion transporter 7 (SLC22A9) increases the import of [3H]estrone-3-sulphate.	[11]

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 anion transporter 7 (SLC22A9).	[1]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Organic anion transporter 7 (SLC22A9).	[14]

25 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 Organic anion transporter 7 (SLC22A9).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the activity of Organic anion transporter 7 (SLC22A9).	[3]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Organic anion transporter 7 (SLC22A9).	[4]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Organic anion transporter 7 (SLC22A9).	[5]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Organic anion transporter 7 (SLC22A9).	[5]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Organic anion transporter 7 (SLC22A9).	[6]
Progesterone	DMUY35B	Approved	Progesterone decreases the activity of Organic anion transporter 7 (SLC22A9).	[7]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone decreases the expression of Organic anion transporter 7 (SLC22A9).	[8]
Aspirin	DM672AH	Approved	Aspirin decreases the activity of Organic anion transporter 7 (SLC22A9).	[3]
Diclofenac	DMPIHLS	Approved	Diclofenac decreases the activity of Organic anion transporter 7 (SLC22A9).	[3]
Piroxicam	DMTK234	Approved	Piroxicam decreases the activity of Organic anion transporter 7 (SLC22A9).	[3]
Indomethacin	DMSC4A7	Approved	Indomethacin decreases the activity of Organic anion transporter 7 (SLC22A9).	[3]
Rifampicin	DM5DSFZ	Approved	Rifampicin decreases the expression of Organic anion transporter 7 (SLC22A9).	[9]
Zidovudine	DM4KI7O	Approved	Zidovudine decreases the expression of Organic anion transporter 7 (SLC22A9).	[10]
Sulindac	DM2QHZU	Approved	Sulindac decreases the activity of Organic anion transporter 7 (SLC22A9).	[3]
Ibuprofen	DM8VCBE	Approved	Ibuprofen decreases the activity of Organic anion transporter 7 (SLC22A9).	[3]
Mefenamic acid	DMK7HFI	Approved	Mefenamic acid decreases the activity of Organic anion transporter 7 (SLC22A9).	[3]
Naproxen	DMZ5RGV	Approved	Naproxen decreases the activity of Organic anion transporter 7 (SLC22A9).	[3]
Ketoprofen	DMRKXPT	Approved	Ketoprofen decreases the activity of Organic anion transporter 7 (SLC22A9).	[3]
Salicyclic acid	DM2F8XZ	Approved	Salicyclic acid decreases the activity of Organic anion transporter 7 (SLC22A9).	[3]
Probenecid	DMMFWOJ	Approved	Probenecid decreases the activity of Organic anion transporter 7 (SLC22A9).	[11]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Organic anion transporter 7 (SLC22A9).	[12]
OTX-015	DMI8RG1	Phase 1/2	OTX-015 decreases the expression of Organic anion transporter 7 (SLC22A9).	[13]
Phenacetin	DMRQAM0	Withdrawn from market	Phenacetin decreases the activity of Organic anion transporter 7 (SLC22A9).	[3]
Phorbol 12,13-butyrate	DMZWTY7	Investigative	Phorbol 12,13-butyrate decreases the activity of Organic anion transporter 7 (SLC22A9).	[7]

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] Interactions of human organic anion transporters and human organic cation transporters with nonsteroidal anti-inflammatory drugs. J Pharmacol Exp Ther. 2002 Nov;303(2):534-9.
• [4] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [5] 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.
• [6] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [7] Regulation of human organic anion transporter 4 by progesterone and protein kinase C in human placental BeWo cells. Am J Physiol Endocrinol Metab. 2007 Jul;293(1):E57-61. doi: 10.1152/ajpendo.00696.2006. Epub 2007 Mar 6.
• [8] 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.
• [9] Rifampin Regulation of Drug Transporters Gene Expression and the Association of MicroRNAs in Human Hepatocytes. Front Pharmacol. 2016 Apr 26;7:111.
• [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] Inhibition of organic anion transporter (OAT) activity by cigarette smoke condensate. Toxicol In Vitro. 2017 Oct;44:27-35.
• [12] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [13] Comprehensive transcriptome profiling of BET inhibitor-treated HepG2 cells. PLoS One. 2022 Apr 29;17(4):e0266966. doi: 10.1371/journal.pone.0266966. eCollection 2022.
• [14] 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.
• [15] Human organic anion transporters mediate the transport of tetracycline. Jpn J Pharmacol. 2002 Jan;88(1):69-76.