Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT4PU620)

• DOT Name: UDP-glucuronosyltransferase 1A4
• Synonyms: UGT1A4; EC 2.4.1.17; Bilirubin-specific UDPGT isozyme 2; hUG-BR2; UDP-glucuronosyltransferase 1-4; UDPGT 1-4; UGT1*4; UGT1-04; UGT1.4; UDP-glucuronosyltransferase 1-D; UGT-1D; UGT1D
• Gene Name: UGT1A4
• UniProt ID: UD14_HUMAN
• EC Number: 2.4.1.17
• Pfam ID: PF00201
• Sequence:
  MARGLQVPLPRLATGLLLLLSVQPWAESGKVLVVPTDGSPWLSMREALRELHARGHQAVV
  LTPEVNMHIKEEKFFTLTAYAVPWTQKEFDRVTLGYTQGFFETEHLLKRYSRSMAIMNNV
  SLALHRCCVELLHNEALIRHLNATSFDVVLTDPVNLCGAVLAKYLSIPAVFFWRYIPCDL
  DFKGTQCPNPSSYIPKLLTTNSDHMTFLQRVKNMLYPLALSYICHTFSAPYASLASELFQ
  REVSVVDLVSYASVWLFRGDFVMDYPRPIMPNMVFIGGINCANGKPLSQEFEAYINASGE
  HGIVVFSLGSMVSEIPEKKAMAIADALGKIPQTVLWRYTGTRPSNLANNTILVKWLPQND
  LLGHPMTRAFITHAGSHGVYESICNGVPMVMMPLFGDQMDNAKRMETKGAGVTLNVLEMT
  SEDLENALKAVINDKSYKENIMRLSSLHKDRPVEPLDLAVFWVEFVMRHKGAPHLRPAAH
  DLTWYQYHSLDVIGFLLAVVLTVAFITFKCCAYGYRKCLGKKGRVKKAHKSKTH
• Function: [Isoform 1]: UDP-glucuronosyltransferase (UGT) that catalyzes phase II biotransformation reactions in which lipophilic substrates are conjugated with glucuronic acid to increase the metabolite's water solubility, thereby facilitating excretion into either the urine or bile. Essential for the elimination and detoxification of drugs, xenobiotics and endogenous compounds. Involved in the glucuronidation of calcidiol, which is the major circulating form of vitamin D3 essential for the regulation of calcium and phosphate homeostasis. Also glucuronidates the biologically active form of vitamin D3, calcitriol, probably leading to its biliary transport and intestinal reabsorption ; [Isoform 2]: Lacks UDP-glucuronosyltransferase (UGT) activity but acts as a negative regulator of isoform 1.
• Tissue Specificity: .Expressed in liver . Expressed in kidney, colon and small intestine . Not expressed in esophagus . Not expressed in skin .; [Isoform 2]: Expressed in liver, kidney, colon, esophagus and small intestine.
• KEGG Pathway:
  Pentose and glucuro.te interconversions (hsa00040)
  Ascorbate and aldarate metabolism (hsa00053)
  Steroid hormone biosynthesis (hsa00140)
  Retinol metabolism (hsa00830)
  Porphyrin metabolism (hsa00860)
  Metabolism of xenobiotics by cytochrome P450 (hsa00980)
  Drug metabolism - cytochrome P450 (hsa00982)
  Drug metabolism - other enzymes (hsa00983)
  Metabolic pathways (hsa01100)
  Biosynthesis of cofactors (hsa01240)
  Bile secretion (hsa04976)
  Chemical carcinogenesis - D. adducts (hsa05204)
  Chemical carcinogenesis - receptor activation (hsa05207)
• Reactome Pathway:
  Heme degradation (R-HSA-189483)
  Defective UGT1A4 causes hyperbilirubinemia (R-HSA-5579016)
  Aspirin ADME (R-HSA-9749641)
  Glucuronidation (R-HSA-156588)
• BioCyc Pathway: MetaCyc:HS11970-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Biotransformations of 20 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Triclosan	DMZUR4N	Approved	UDP-glucuronosyltransferase 1A4 increases the glucuronidation of Triclosan.	[16]
Diclofenac	DMPIHLS	Approved	UDP-glucuronosyltransferase 1A4 increases the glucuronidation of Diclofenac.	[17]
Nicotine	DMWX5CO	Approved	UDP-glucuronosyltransferase 1A4 increases the glucuronidation of Nicotine.	[18]
Clozapine	DMFC71L	Approved	UDP-glucuronosyltransferase 1A4 increases the glucuronidation of Clozapine.	[19]
Indomethacin	DMSC4A7	Approved	UDP-glucuronosyltransferase 1A4 increases the glucuronidation of Indomethacin.	[17]
Sulindac	DM2QHZU	Approved	UDP-glucuronosyltransferase 1A4 increases the glucuronidation of Sulindac.	[17]
Ursodeoxycholic acid	DMCUT21	Approved	UDP-glucuronosyltransferase 1A4 increases the glucuronidation of Ursodeoxycholic acid.	[20]
Imipramine	DM2NUH3	Approved	UDP-glucuronosyltransferase 1A4 increases the glucuronidation of Imipramine.	[18]
Flurbiprofen	DMGN4BY	Approved	UDP-glucuronosyltransferase 1A4 increases the glucuronidation of Flurbiprofen.	[17]
Ketoprofen	DMRKXPT	Approved	UDP-glucuronosyltransferase 1A4 increases the glucuronidation of Ketoprofen.	[17]
Lamotrigine	DM8SXYG	Approved	UDP-glucuronosyltransferase 1A4 increases the glucuronidation of Lamotrigine.	[10]
Cotinine	DMCEZ1B	Approved	UDP-glucuronosyltransferase 1A4 increases the glucuronidation of Cotinine.	[18]
EXISULIND	DMBY56U	Phase 3	UDP-glucuronosyltransferase 1A4 increases the glucuronidation of EXISULIND.	[17]
Ranirestat	DMD5QRS	Phase 3	UDP-glucuronosyltransferase 1A4 increases the glucuronidation of Ranirestat.	[21]
Androsterone	DMITJAK	Phase 3	UDP-glucuronosyltransferase 1A4 increases the glucuronidation of Androsterone.	[19]
Arachidonic acid	DMUOQZD	Investigative	UDP-glucuronosyltransferase 1A4 increases the glucuronidation of Arachidonic acid.	[22]
BRN-3548355	DM4KXT0	Investigative	UDP-glucuronosyltransferase 1A4 increases the glucuronidation of BRN-3548355.	[23]
Farnesol	DMV2X1B	Investigative	UDP-glucuronosyltransferase 1A4 increases the glucuronidation of Farnesol.	[24]
BETULIN	DMGQRON	Investigative	UDP-glucuronosyltransferase 1A4 increases the glucuronidation of BETULIN.	[16]
20-HETE	DM5BAJ9	Investigative	UDP-glucuronosyltransferase 1A4 increases the glucuronidation of 20-HETE.	[22]

1 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 UDP-glucuronosyltransferase 1A4.	[1]

14 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of UDP-glucuronosyltransferase 1A4.	[2]
Phenobarbital	DMXZOCG	Approved	Phenobarbital increases the activity of UDP-glucuronosyltransferase 1A4.	[3]
Troglitazone	DM3VFPD	Approved	Troglitazone decreases the expression of UDP-glucuronosyltransferase 1A4.	[4]
Obeticholic acid	DM3Q1SM	Approved	Obeticholic acid decreases the expression of UDP-glucuronosyltransferase 1A4.	[5]
Omeprazole	DM471KJ	Approved	Omeprazole increases the expression of UDP-glucuronosyltransferase 1A4.	[6]
Trifluoperazine	DMKBYWI	Approved	Trifluoperazine increases the activity of UDP-glucuronosyltransferase 1A4.	[7]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of UDP-glucuronosyltransferase 1A4.	[8]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of UDP-glucuronosyltransferase 1A4.	[9]
PIRINIXIC ACID	DM82Y75	Preclinical	PIRINIXIC ACID increases the expression of UDP-glucuronosyltransferase 1A4.	[10]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of UDP-glucuronosyltransferase 1A4.	[11]
Butanoic acid	DMTAJP7	Investigative	Butanoic acid increases the expression of UDP-glucuronosyltransferase 1A4.	[12]
USNIC ACID	DMGOURX	Investigative	USNIC ACID increases the expression of UDP-glucuronosyltransferase 1A4.	[13]
AMENTOFLAVONE	DMLRNV2	Investigative	AMENTOFLAVONE decreases the activity of UDP-glucuronosyltransferase 1A4.	[14]
pregnenolone-16alpha-carbonitrile	DM0LW7G	Investigative	pregnenolone-16alpha-carbonitrile increases the expression of UDP-glucuronosyltransferase 1A4.	[15]

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] UDP-glucuronosyltransferase 1A6 overexpression in breast cancer cells resistant to methotrexate. Biochem Pharmacol. 2011 Jan 1;81(1):60-70.
• [3] Studies on induction of lamotrigine metabolism in transgenic UGT1 mice. Xenobiotica. 2009 Nov;39(11):826-35.
• [4] Increased sensitivity for troglitazone-induced cytotoxicity using a human in vitro co-culture model. Toxicol In Vitro. 2009 Oct;23(7):1387-95.
• [5] Pharmacotoxicology of clinically-relevant concentrations of obeticholic acid in an organotypic human hepatocyte system. Toxicol In Vitro. 2017 Mar;39:93-103.
• [6] Use of mRNA expression to detect the induction of drug metabolising enzymes in rat and human hepatocytes. Toxicol Appl Pharmacol. 2009 Feb 15;235(1):86-96.
• [7] Assessment of the inhibition potential of Licochalcone A against human UDP-glucuronosyltransferases. Food Chem Toxicol. 2016 Apr;90:112-22.
• [8] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [9] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [10] Expression of the human UGT1 locus in transgenic mice by 4-chloro-6-(2,3-xylidino)-2-pyrimidinylthioacetic acid (WY-14643) and implications on drug metabolism through peroxisome proliferator-activated receptor alpha activation. Drug Metab Dispos. 2007 Mar;35(3):419-27.
• [11] Bisphenol A-associated alterations in the expression and epigenetic regulation of genes encoding xenobiotic metabolizing enzymes in human fetal liver. Environ Mol Mutagen. 2014 Apr;55(3):184-95.
• [12] Butyrate interacts with benzo[a]pyrene to alter expression and activities of xenobiotic metabolizing enzymes involved in metabolism of carcinogens within colon epithelial cell models. Toxicology. 2019 Jan 15;412:1-11.
• [13] Effects of usnic acid exposure on human hepatoblastoma HepG2 cells in culture. J Appl Toxicol. 2012 Sep;32(9):722-30.
• [14] Amentoflavone is a potent broad-spectrum inhibitor of human UDP-glucuronosyltransferases. Chem Biol Interact. 2018 Mar 25;284:48-55.
• [15] Tissue-specific, inducible, and hormonal control of the human UDP-glucuronosyltransferase-1 (UGT1) locus. J Biol Chem. 2005 Nov 11;280(45):37547-57.
• [16] Phase II metabolism of betulin by rat and human UDP-glucuronosyltransferases and sulfotransferases. Chem Biol Interact. 2019 Apr 1;302:190-195. doi: 10.1016/j.cbi.2019.02.009. Epub 2019 Feb 15.
• [17] Glucuronidation of nonsteroidal anti-inflammatory drugs: identifying the enzymes responsible in human liver microsomes. Drug Metab Dispos. 2005 Jul;33(7):1027-35.
• [18] N-glucuronidation of nicotine and cotinine by human liver microsomes and heterologously expressed UDP-glucuronosyltransferases. Drug Metab Dispos. 2003 Nov;31(11):1361-8. doi: 10.1124/dmd.31.11.1361.
• [19] UDP-glucuronosyltransferase 1A4 polymorphisms in a Japanese population and kinetics of clozapine glucuronidation. Drug Metab Dispos. 2005 May;33(5):672-5. doi: 10.1124/dmd.104.002576. Epub 2005 Feb 11.
• [20] UGT-dependent regioselective glucuronidation of ursodeoxycholic acid and obeticholic acid and selective transport of the consequent acyl glucuronides by OATP1B1 and 1B3. Chem Biol Interact. 2019 Sep 1;310:108745. doi: 10.1016/j.cbi.2019.108745. Epub 2019 Jul 9.
• [21] Uridine diphosphate sugar-selective conjugation of an aldose reductase inhibitor (AS-3201) by UDP-glucuronosyltransferase 2B subfamily in human liver microsomes. Biochem Pharmacol. 2004 Apr 1;67(7):1269-78. doi: 10.1016/j.bcp.2003.11.010.
• [22] Glucuronidation of oxidized fatty acids and prostaglandins B1 and E2 by human hepatic and recombinant UDP-glucuronosyltransferases. J Lipid Res. 2004 Sep;45(9):1694-703. doi: 10.1194/jlr.M400103-JLR200. Epub 2004 Jul 1.
• [23] Correlation between UDP-glucuronosyltransferase genotypes and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone glucuronidation phenotype in human liver microsomes. Cancer Res. 2004 Feb 1;64(3):1190-6. doi: 10.1158/0008-5472.can-03-3219.
• [24] Farnesol is glucuronidated in human liver, kidney and intestine in vitro, and is a novel substrate for UGT2B7 and UGT1A1. Biochem J. 2004 Dec 15;384(Pt 3):637-45. doi: 10.1042/BJ20040997.