Details of Drug-Metabolizing Enzyme (DME)

General Information of DME (ID: DME0048)
DME Name UDP-glucuronosyltransferase 1A4 (UGT1A4), Homo sapiens
Synonyms UDP-glucuronosyltransferase family 1 member A4; UDP-glucuronosyltransferase 1-D; UDP-glucuronosyltransferase 1-4; Bilirubin-specific UDPGT isozyme 2; UDPGT 1-4; UGT-1D; UGT1*4; UGT1-04; UGT1.4; UGT1A4; UGT1D; hUG-BR2
Gene Name UGT1A4
UniProt ID
UD14_HUMAN
Gene ID
54657
EC Number    EC: 2.4.1.17     (Click to Show/Hide the Complete EC Tree)
Transferase
Glycosyltransferases
Hexosyltransferase
EC: 2.4.1.17
Lineage    Species: Homo sapiens     (Click to Show/Hide the Complete Species Lineage)
Kingdom: Metazoa
Phylum: Chordata
Class: Mammalia
Order: Primates
Family: Hominidae
Genus: Homo
Species: Homo sapiens
Interactome
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       Interactions between Xenobiotics and DME (XEOTIC)                      
Jump to Detailed Interactome Data                      
       Interactions between Host Protein and DME (HOSPPI)                     
Jump to Detailed Interactome Data                      
      Click to Show/Hide the Molecular/Functional Data (Sequence/Structure/Pathway/Function) of This DME
Sequence
MARGLQVPLPRLATGLLLLLSVQPWAESGKVLVVPTDGSPWLSMREALRELHARGHQAVV
LTPEVNMHIKEEKFFTLTAYAVPWTQKEFDRVTLGYTQGFFETEHLLKRYSRSMAIMNNV
SLALHRCCVELLHNEALIRHLNATSFDVVLTDPVNLCGAVLAKYLSIPAVFFWRYIPCDL
DFKGTQCPNPSSYIPKLLTTNSDHMTFLQRVKNMLYPLALSYICHTFSAPYASLASELFQ
REVSVVDLVSYASVWLFRGDFVMDYPRPIMPNMVFIGGINCANGKPLSQEFEAYINASGE
HGIVVFSLGSMVSEIPEKKAMAIADALGKIPQTVLWRYTGTRPSNLANNTILVKWLPQND
LLGHPMTRAFITHAGSHGVYESICNGVPMVMMPLFGDQMDNAKRMETKGAGVTLNVLEMT
SEDLENALKAVINDKSYKENIMRLSSLHKDRPVEPLDLAVFWVEFVMRHKGAPHLRPAAH
DLTWYQYHSLDVIGFLLAVVLTVAFITFKCCAYGYRKCLGKKGRVKKAHKSKTH
Pathway Ascorbate and aldarate metabolism (hsa00053 )
Chemical carcinogenesis (hsa05204 )
Drug metabolism - cytochrome P450 (hsa00982 )
Drug metabolism - other enzymes (hsa00983 )
Metabolic pathways (hsa01100 )
Metabolism of xenobiotics by cytochrome P450 (hsa00980 )
Pentose and glucuronate interconversions (hsa00040 )
Porphyrin and chlorophyll metabolism (hsa00860 )
Retinol metabolism (hsa00830 )
Steroid hormone biosynthesis (hsa00140 )
Function This enzyme glucuronidates bilirubin IX-alpha to form both the IX-alpha-C8 and IX-alpha-C12 monoconjugates and diconjugate.
Full List of Drug(s) Metabolized by This DME
      Drugs Approved by FDA Click to Show/Hide the Full List of Drugs:        32 Drugs
Bupropion
 Drug Info Approved Nicotine dependence ICD11: 6C4A [1]
Yn-968D1
 Drug Info Approved Breast cancer ICD11: 2C60-2C6Y [2]
Ethinyl estradiol
 Drug Info Approved Menopausal disorder ICD11: GA30 [3]
Aprepitant
 Drug Info Approved Functional nausea/vomiting ICD11: DD90 [4]
Asenapine maleate
 Drug Info Approved Schizophrenia ICD11: 6A20 [5]
Cyproheptadine
 Drug Info Approved Rheumatoid arthritis ICD11: FA20 [6]
Axitinib
 Drug Info Approved Renal cell carcinoma ICD11: 2C90 [7]
Finasteride
 Drug Info Approved Prostatic hyperplasia ICD11: GA90 [8]
Bromfenac
 Drug Info Approved Cataract ICD11: 9B10 [9]
Dexmedetomidine hydrochloride
 Drug Info Approved Tension headache ICD11: 8A81 [10]
Eslicarbazepine acetate
 Drug Info Approved Epilepsy ICD11: 8A60 [11]
Midazolam hydrochloride
 Drug Info Approved Anxiety disorder ICD11: 6B00 [12], [13], [14]
Pexidartinib
 Drug Info Approved Neurofibromatosis ICD11: LD2D [15]
Phenytoin
 Drug Info Approved Epilepsy ICD11: 8A60 [16]
Rilpivirine hydrochloride
 Drug Info Approved Human immunodeficiency virus infection ICD11: 1C60 [17]
Sarpogrelate
 Drug Info Approved Diabetic complication ICD11: 5A2Y [18]
Anastrozole
 Drug Info Approved Breast cancer ICD11: 2C60 [19]
Clofazimine
 Drug Info Approved Crohn disease ICD11: DD70 [20]
Clozapine
 Drug Info Approved Schizophrenia ICD11: 6A20 [21]
Tecovirimat
 Drug Info Approved Smallpox ICD11: 1E70 [22]
Tecovirimat
 Drug Info Approved Smallpox ICD11: 1E70 [23]
Calcitriol
 Drug Info Approved Congenital alopecia ICD11: LC30 [24]
Cyclizine
 Drug Info Approved Nausea ICD11: MD90 [25]
Itraconazole
 Drug Info Approved Blastomycosis ICD11: 1F22 [26]
Ketotifen
 Drug Info Approved Conjunctivitis ICD11: 9A60 [27]
Ketotifen
 Drug Info Approved Conjunctivitis ICD11: 9A60 [28]
Lamotrigine
 Drug Info Approved Bipolar disorder ICD11: 6A60 [29]
Trimipramine
 Drug Info Approved Depression ICD11: 6A71 [30]
Fulvestrant
 Drug Info Approved Breast cancer ICD11: 2C60 [31]
Lorlatinib
 Drug Info Approved Lung cancer ICD11: 2C25 [32]
Osilodrostat
 Drug Info Approved Cushing syndrome ICD11: 5A70 [33]
Posaconazole
 Drug Info Approved Candidiasis ICD11: 1F23 [34]
      Drugs in Phase 4 Clinical Trial Click to Show/Hide the Full List of Drugs:          1 Drugs
Retigabine
 Drug Info Phase 4 Epilepsy ICD11: 8A60 [35], [36], [37]
      Drugs in Phase 3 Clinical Trial Click to Show/Hide the Full List of Drugs:          3 Drugs
ABL001
 Drug Info Phase 3 Chronic myelogenous leukaemia ICD11: 2A20 [38]
AZD-2171
 Drug Info Phase 3 Lung cancer ICD11: 2C25 [39]
Ag-221
 Drug Info Phase 3 Acute myelogenous leukaemia ICD11: 2A41 [40]
      Drugs in Phase 2 Clinical Trial Click to Show/Hide the Full List of Drugs:          5 Drugs
PF-06463922
 Drug Info Phase 2 Lung cancer ICD11: 2C25 [41]
ABT-126
 Drug Info Phase 2 Alzheimer disease ICD11: 8A20 [42]
AMG 232
 Drug Info Phase 2 Merkel cell carcinoma ICD11: 2C34 [43]
MPC-4326
 Drug Info Phase 2 Human immunodeficiency virus infection ICD11: 1C60 [44]
ABT-751
 Drug Info Phase 2 Breast cancer ICD11: 2C60 [45]
      Drugs in Phase 1 Clinical Trial Click to Show/Hide the Full List of Drugs:          1 Drugs
LM-94
 Drug Info Phase 1/2 Cholangitis ICD11: DC13 [46]
      Discontinued/withdrawn Drugs Click to Show/Hide the Full List of Drugs:          1 Drugs
Motesanib
 Drug Info Discontinued in Phase 3 Lung cancer ICD11: 2C25 [47]
      Preclinical/investigative Agents Click to Show/Hide the Full List of Drugs:          2 Drugs
Cotinine
 Drug Info Investigative Nicotine dependence ICD11: 6C4A [48]
UDP-glucuronate
 Drug Info Investigative Discovery agent ICD: N.A. [46]
      Experimental Enzyme Kinetic Data of Drugs Click to Show/Hide the Full List of Drugs:          3 Drugs
Calcitriol
 Drug Info Approved Congenital alopecia Km = 0.0073 microM [24]
LM-94
 Drug Info Phase 1/2 Cholangitis Km = 0.00012 microM [46]
UDP-glucuronate
 Drug Info Investigative Discovery agent Km = 0.00025 microM [46]
Full List of Metabolic Reactions (MR) Catalyzed by This DME
MR ID Reactant Product MR Type Source Drug REF
MR008317 ABT-126 ABT-126 metabolite M11 Conjugation - Glucuronidation ABT-126 [42]
MR007242 ABT-751 ABT-751 glucuronide Unclear - Unclear ABT-751 [45]
MR002975 Aprepitant Aprepitant glucuronide Conjugation - Glucuronidation Aprepitant [4]
MR000328 Asenapine maleate Asenapine-N-glucuronide Conjugation - N-Glucuronidation Asenapine maleate [49]
MR010077 Atipamezole Atipamezole Metabolite M1 Conjugation - N-glucuronidation Atipamezole [50]
MR009888 Axitinib Axitinib Metabolite M7 Unclear - Unclear axitinib [7]
MR000338 AZD-2171 AZD-2171 metabolite M3 Conjugation - N-Glucuronidation AZD-2171 [39]
MR000461 Bromfenac Bromfenac glucuronide intemediate Unclear - Unclear Bromfenac [51], [52]
MR000506 R,R-threohydrobupropion R,R-threohydrobupropion glucuronide Conjugation - Glucuronidation Bupropion [1]
MR000510 R,S-erythrohydrobupropion R,S-erythrohydrobupropion glucuronide Conjugation - Glucuronidation Bupropion [1]
MR000511 S,R-erythrohydrobupropion S,R-erythrohydrobupropion glucuronide Conjugation - Glucuronidation Bupropion [1]
MR002817 Calcitriol Calcitriol 25-O-glucuronide Conjugation - Glucuronidation Calcitriol [24]
MR006560 Hydrolytic-deaminated clofazimine Hydrolytic-deaminated clofazimine glucuronide Conjugation - Glucuronidation Clofazimine [20]
MR002837 Clozapine Clozapine glucuronide Conjugation - Glucuronidation Clozapine [21]
MR005303 Cotinine Cotinine-N-glucuronide Conjugation - Glucuronidation Cotinine [48]
MR004135 Cyproheptadine Cyproheptadine N-glucuronide Conjugation - N-glucuronidation Cyproheptadine [6]
MR000804 Dexmedetomidine hydrochloride Dexmedetomidine N-glucuronidation Conjugation - Glucuronidation Dexmedetomidine hydrochloride [10]
MR002720 Ethinyl estradiol N-desmethylzopiclone Conjugation - O-Glucuronidation Ethinyl estradiol [3]
MR001031 Omega-hydroxyfinasteride Hydroxyfinasteride glucuronide Conjugation - Glucuronidation Finasteride [8]
MR003165 Hydroxyphenytoin Hydroxyphenytoin-O-glucuronide metabolite Unclear - Unclear Fosphenytoin sodium [53]
MR001376 Ketotifen Ketotifen-N-glucuronide Conjugation - N-Glucuronidation Ketotifen [27], [28]
MR001410 Lamotrigine Lamotrigine-2-N-glucuronide Conjugation - Glucuronidation Lamotrigine [54], [55], [56]
MR001411 Lamotrigine Lamotrigine-5-N-glucuronide Conjugation - Glucuronidation Lamotrigine [54], [29], [56]
MR006135 LM-94 4-Methylumbelliferyl glucuronide Conjugation - Conjugation LM-94 [57]
MR001651 17alpha-Ethinylestradiol N-desmethylzopiclone metabolite Conjugation - O-Glucuronidation Mestranol [58], [3], [59]
MR004745 Midazolam hydrochloride 1-hydroxymidazolam glucuronide Conjugation - N-glucuronidation Midazolam hydrochloride [12], [13], [14]
MR004746 Midazolam hydrochloride 4-hydroxymidazolam glucuronide Conjugation - N-glucuronidation Midazolam hydrochloride [12], [13]
MR009731 Motesanib Motesanib M1 Conjugation - Glucuronidation Motesanib [47]
MR009658 MPC-4326 Mono-BVMG () Conjugation - Glucuronidation MPC-4326 [60]
MR009658 MPC-4326 Mono-BVMG () Conjugation - Glucuronidation MPC-4326 [44]
MR009659 MPC-4326 Mono-BVMG () Conjugation - Glucuronidation MPC-4326 [44]
MR009660 MPC-4326 Di-BVMG Conjugation - Glucuronidation MPC-4326 [44]
MR008871 Osilodrostat Osilodrostat glucuronide Unclear - Unclear Osilodrostat [33]
MR002871 Pexidartinib N-glucuronide?metabolite Conjugation - Glucuronidation Pexidartinib [15]
MR011750 PF-06463922 PF-06895751 (M8) Unclear - Unclear PF-06463922 [41]
MR002031 Hydroxyphenytoin 4-hydroxyphenytoin o-glucuronide Conjugation - O-Glucuronidation Phenytoin [16], [61]
MR002087 Posaconazole Posaconazole-glucuronide Conjugation - Glucuronidation Posaconazole [62]
MR005236 Retigabine Retigabine-N2-glucuronide Conjugation - Glucuronidation Retigabine [35], [36], [37]
MR005237 Retigabine Retigabine-N4-glucuronide Conjugation - Glucuronidation Retigabine [35], [36], [37]
MR009538 Rilpivirine hydrochloride Rilpivirine M5 Conjugation - Glucuronidation Rilpivirine hydrochloride [17]
MR008971 Sarpogrelate metabolite M-1 M-1 N-glucuronide Conjugation - Glucuronidation Sarpogrelate [18]
MR002354 Tecovirimat . Hydrolysis - Hydrolysis Tecovirimat [22]
MR002497 Valproic acid Valproic acid beta-O-glucuronide metabolite Oxidation - Dehydrogenation Valproic acid [63]
⏷ Show the Full List of 43 MR(s)
References
1 DrugBank(Pharmacology-Metabolism)Bupropion
2 Metabolism and pharmacokinetics of novel selective vascular endothelial growth factor receptor-2 inhibitor apatinib in humans
3 Human bilirubin UDP-glucuronosyltransferase catalyzes the glucuronidation of ethinylestradiol Mol Pharmacol. 1993 Apr;43(4):649-54.
4 In vitro glucuronidation of aprepitant: a moderate inhibitor of UGT2B7 Xenobiotica. 2015;45(11):990-8. doi: 10.3109/00498254.2015.1038743.
5 Asenapine for the treatment of manic and mixed episodes associated with bipolar I disorder: from clinical research to clinical practice. Expert Opin Pharmacother. 2013 Mar;14(4):489-504.
6 Human metabolism of cyproheptadine
7 In Vitro Kinetic Characterization of Axitinib Metabolism
8 Finasteride for hair loss: a review J Dermatolog Treat. 2022 Jun;33(4):1938-1946. doi: 10.1080/09546634.2021.1959506.
9 Metabolite Profiling and Reaction Phenotyping for the in Vitro Assessment of the Bioactivation of Bromfenac ? Chem Res Toxicol. 2020 Jan 21;33(1):249-257. doi: 10.1021/acs.chemrestox.9b00268.
10 Large inter-individual variability in pharmacokinetics of dexmedetomidine and its two major N-glucuronides in adult intensive care unit patients J Pharm Biomed Anal. 2019 Oct 25;175:112777. doi: 10.1016/j.jpba.2019.07.025.
11 Pharmacokinetics and drug interactions of eslicarbazepine acetate Epilepsia. 2012 Jun;53(6):935-46. doi: 10.1111/j.1528-1167.2012.03519.x.
12 The inhibition study of human UDP-glucuronosyltransferases with cytochrome P450 selective substrates and inhibitors
13 Contribution of the N-glucuronidation pathway to the overall in vitro metabolic clearance of midazolam in humans
14 The Oral Bioavailability and Metabolism of Midazolam in Stable Critically Ill Children: A Pharmacokinetic Microtracing Study
15 FDA label of Pexidartinib. The 2020 official website of the U.S. Food and Drug Administration.
16 Pharmacogenomics knowledge for personalized medicine Clin Pharmacol Ther. 2012 Oct;92(4):414-7. doi: 10.1038/clpt.2012.96.
17 Human biotransformation of the nonnucleoside reverse transcriptase inhibitor rilpivirine and a cross-species metabolism comparison. Antimicrob Agents Chemother. 2013 Oct;57(10):5067-79.
18 Glucuronidation of a sarpogrelate active metabolite is mediated by UDP-glucuronosyltransferases 1A4, 1A9, and 2B4
19 In vitro and in vivo oxidative metabolism and glucuronidation of anastrozole. Br J Clin Pharmacol. 2010 Dec;70(6):854-69.
20 Characterization of Clofazimine Metabolism in Human Liver Microsomal Incubation In Vitro
21 DrugBank(Pharmacology-Metabolism)Clozapine
22 LABEL:POXX- tecovirimat monohydrate injection, solution, concentrate TPOXX- tecovirimat monohydrate capsule
23 DrugBank(Pharmacology-Metabolism):Tecovirimat
24 Identification of human UDP-glucuronosyltransferases catalyzing hepatic 1alpha,25-dihydroxyvitamin D3 conjugation. Biochem Pharmacol. 2008 Mar 1;75(5):1240-50.
25 N-glucuronidation catalyzed by UGT1A4 and UGT2B10 in human liver microsomes: Assay optimization and substrate identification
26 Investigation into UDP-glucuronosyltransferase (UGT) enzyme kinetics of imidazole- and triazole-containing antifungal drugs in human liver microsomes and recombinant UGT enzymes. Drug Metab Dispos. 2010 Jun;38(6):923-9.
27 N+-glucuronidation, a common pathway in human metabolism of drugs with a tertiary amine group Drug Metab Dispos. 1998 Sep;26(9):830-7.
28 Human UDP-glucuronosyltransferase (UGT) 2B10 in drug N-glucuronidation: substrate screening and comparison with UGT1A3 and UGT1A4. Drug Metab Dispos. 2013 Jul;41(7):1389-97.
29 Studies on induction of lamotrigine metabolism in transgenic UGT1 mice. Xenobiotica. 2009 Nov;39(11):826-35.
30 Role of human UGT2B10 in N-glucuronidation of tricyclic antidepressants, amitriptyline, imipramine, clomipramine, and trimipramine. Drug Metab Dispos. 2010 May;38(5):863-70.
31 Inactivation of the pure antiestrogen fulvestrant and other synthetic estrogen molecules by UDP-glucuronosyltransferase 1A enzymes expressed in breast tissue. Mol Pharmacol. 2006 Mar;69(3):908-20.
32 FDA label of Lorlatinib. The 2020 official website of the U.S. Food and Drug Administration.
33 DrugBank(Pharmacology-Metabolism):Osilodrostat
34 Identification of human UDP-glucuronosyltransferase enzyme(s) responsible for the glucuronidation of posaconazole (Noxafil) Drug Metab Dispos. 2004 Feb;32(2):267-71. doi: 10.1124/dmd.32.2.267.
35 Retigabine: the newer potential antiepileptic drug
36 Retigabine N-glucuronidation and its potential role in enterohepatic circulation. Drug Metab Dispos. 1999 May;27(5):605-12.
37 N-Glucuronidation of the antiepileptic drug retigabine: results from studies with human volunteers, heterologously expressed human UGTs, human liver, kidney, and liver microsomal membranes of Crigler-Najjar type II. Metabolism. 2006 Jun;55(6):711-21.
38 Pharmacokinetic drug interactions of asciminib with the sensitive cytochrome P450 probe substrates midazolam, warfarin, and repaglinide in healthy participants
39 In vitro hepatic metabolism of cediranib, a potent vascular endothelial growth factor tyrosine kinase inhibitor: interspecies comparison and human enzymology. Drug Metab Dispos. 2010 Oct;38(10):1688-97.
40 DrugBank(Pharmacology-Metabolism):Ag-221
41 The Effect of Modafinil on the Safety and Pharmacokinetics of Lorlatinib: A Phase I Study in Healthy Participants
42 Metabolism and Disposition of a Novel Selective 7 Neuronal Acetylcholine Receptor Agonist ABT-126 in Humans: Characterization of the Major Roles for Flavin-Containing Monooxygenases and UDP-Glucuronosyl Transferase 1A4 and 2B10 in Catalysis
43 Pharmacokinetics and metabolism of AMG 232, a novel orally bioavailable inhibitor of the MDM2-p53 interaction, in rats, dogs and monkeys: in vitro-in vivo correlation
44 Bevirimat: a novel maturation inhibitor for the treatment of HIV-1 infection. Antivir Chem Chemother. 2008;19(3):107-13.
45 Preclinical discovery of candidate genes to guide pharmacogenetics during phase I development: the example of the novel anticancer agent ABT-751. Pharmacogenet Genomics. 2013 Jul;23(7):374-81.
46 Identification of aspartic acid and histidine residues mediating the reaction mechanism and the substrate specificity of the human UDP-glucuronosyltransferases 1A. J Biol Chem. 2007 Dec 14;282(50):36514-24.
47 In vitro metabolism of the novel, highly selective oral angiogenesis inhibitor motesanib diphosphate in preclinical species and in humans
48 Interindividual variability in nicotine metabolism: C-oxidation and glucuronidation
49 Asenapine review, part I: chemistry, receptor affinity profile, pharmacokinetics and metabolism. Expert Opin Drug Metab Toxicol. 2014 Jun;10(6):893-903.
50 Assessment and Confirmation of Species Difference in Nonlinear Pharmacokinetics of Atipamezole with Physiologically Based Pharmacokinetic Modeling
51 Metabolite profiling and reaction phenotyping for the in vitro assessment of the bioactivation of bromfenac. Chem Res Toxicol. 2020 Jan 21;33(1):249-257.
52 Metabolic disposition of 14C-bromfenac in healthy male volunteers J Clin Pharmacol. 1998 Aug;38(8):744-52. doi: 10.1002/j.1552-4604.1998.tb04815.x.
53 U. S. FDA Label -Fosphenytoin sodium
54 Pharmacokinetics, toxicology and safety of lamotrigine in epilepsy Expert Opin Drug Metab Toxicol. 2006 Dec;2(6):1009-18. doi: 10.1517/17425255.2.6.1009.
55 Simultaneous determination of plasma lamotrigine, lamotrigine N2-glucuronide and lamotrigine N2-oxide by UHPLC-MS/MS in epileptic patients. J Pharm Biomed Anal. 2022 Oct 25;220:115017. doi: 10.1016/j.jpba.2022.115017.
56 UDP-glucuronosyltransferase 1A4-mediated N2-glucuronidation is the major metabolic pathway of lamotrigine in chimeric NOG-TKm30 mice with humanised-livers. Xenobiotica. 2021 Oct;51(10):1146-1154. doi: 10.1080/00498254.2021.1972492.
57 Comparisons of detections, stabilities, and kinetics of degradation of hymecromone and its glucuronide and sulfate metabolites
58 Genetic variation in the first-pass metabolism of ethinylestradiol, sex hormone binding globulin levels and venous thrombosis risk Eur J Intern Med. 2017 Jul;42:54-60. doi: 10.1016/j.ejim.2017.05.019.
59 The potent inhibition of human cytosolic sulfotransferase 1A1 by 17-ethinylestradiol is due to interactions with isoleucine 89 on loop 1 Horm Mol Biol Clin Investig. 2014 Dec;20(3):81-90. doi: 10.1515/hmbci-2014-0028.
60 Glucuronidation of anti-HIV drug candidate bevirimat: identification of human UDP-glucuronosyltransferases and species differences
61 Biotransformation of phenytoin in the electrochemically-driven CYP2C19 system. Biophys Chem. 2022 Dec;291:106894. doi: 10.1016/j.bpc.2022.106894.
62 Identification of human UDP-glucuronosyltransferase enzyme(s) responsible for the glucuronidation of posaconazole (Noxafil). Drug Metab Dispos. 2004 Feb;32(2):267-71.
63 Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675.

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