Details of Drug Off-Target (DOT)

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

DOT Name UDP-glucuronosyltransferase 1A8
Synonyms UGT1A8; EC 2.4.1.17; UDP-glucuronosyltransferase 1-8; UDPGT 1-8; UGT1*8; UGT1-08; UGT1.8; UDP-glucuronosyltransferase 1-H; UGT-1H; UGT1H
Gene Name UGT1A8
UniProt ID
UD18_HUMAN
3D Structure
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2D Sequence (FASTA)
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3D Structure (PDB)
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EC Number
2.4.1.17
Pfam ID
PF00201
Sequence
MARTGWTSPIPLCVSLLLTCGFAEAGKLLVVPMDGSHWFTMQSVVEKLILRGHEVVVVMP
EVSWQLGKSLNCTVKTYSTSYTLEDLDREFMDFADAQWKAQVRSLFSLFLSSSNGFFNLF
FSHCRSLFNDRKLVEYLKESSFDAVFLDPFDACGLIVAKYFSLPSVVFARGIACHYLEEG
AQCPAPLSYVPRILLGFSDAMTFKERVRNHIMHLEEHLFCQYFSKNALEIASEILQTPVT
AYDLYSHTSIWLLRTDFVLDYPKPVMPNMIFIGGINCHQGKPLPMEFEAYINASGEHGIV
VFSLGSMVSEIPEKKAMAIADALGKIPQTVLWRYTGTRPSNLANNTILVKWLPQNDLLGH
PMTRAFITHAGSHGVYESICNGVPMVMMPLFGDQMDNAKRMETKGAGVTLNVLEMTSEDL
ENALKAVINDKSYKENIMRLSSLHKDRPVEPLDLAVFWVEFVMRHKGAPHLRPAAHDLTW
YQYHSLDVIGFLLAVVLTVAFITFKCCAYGYRKCLGKKGRVKKAHKSKTH
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. Catalyzes the glucuronidation of endogenous steroid hormones such as androgens and estrogens. Produces dihydrotestosterone (DHT) diglucuronide from the DHT after two subsequent glucoronidation steps. Also catalyzes the glucuronidation of the isoflavones genistein, daidzein, glycitein, formononetin, biochanin A and prunetin, which are phytoestrogens with anticancer and cardiovascular properties. Involved in the glucuronidation of the AGTR1 angiotensin receptor antagonist caderastan, a drug which can inhibit the effect of angiotensin II. Also metabolizes mycophenolate, an immunosuppressive agent ; [Isoform 2]: Lacks UGT glucuronidation activity but acts as a negative regulator of isoform 1.
Tissue Specificity .Expressed in kidney, colon and small intestine . Not expressed in liver .; [Isoform 2]: Expressed in liver, kidney, colon 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
Aspirin ADME (R-HSA-9749641 )
Glucuronidation (R-HSA-156588 )
BioCyc Pathway
MetaCyc:HS10706-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

Molecular Interaction Atlas (MIA) Jump to Detail Molecular Interaction Atlas of This DOT
This DOT Affected the Biotransformations of 59 Drug(s)
Drug Name Drug ID Highest Status Interaction REF
Acetaminophen DMUIE76 Approved UDP-glucuronosyltransferase 1A8 increases the glucuronidation of Acetaminophen. [21]
Estradiol DMUNTE3 Approved UDP-glucuronosyltransferase 1A8 increases the glucuronidation of Estradiol. [21]
Quercetin DM3NC4M Approved UDP-glucuronosyltransferase 1A8 increases the glucuronidation of Quercetin. [22]
Diethylstilbestrol DMN3UXQ Approved UDP-glucuronosyltransferase 1A8 increases the glucuronidation of Diethylstilbestrol. [23]
Aspirin DM672AH Approved UDP-glucuronosyltransferase 1A8 increases the glucuronidation of Aspirin. [21]
Etoposide DMNH3PG Approved UDP-glucuronosyltransferase 1A8 increases the glucuronidation of Etoposide. [24]
Irinotecan DMP6SC2 Approved UDP-glucuronosyltransferase 1A8 increases the glucuronidation of Irinotecan. [25]
Diclofenac DMPIHLS Approved UDP-glucuronosyltransferase 1A8 increases the glucuronidation of Diclofenac. [21]
Indomethacin DMSC4A7 Approved UDP-glucuronosyltransferase 1A8 increases the glucuronidation of Indomethacin. [21]
Ethinyl estradiol DMODJ40 Approved UDP-glucuronosyltransferase 1A8 increases the glucuronidation of Ethinyl estradiol. [26]
Sulindac DM2QHZU Approved UDP-glucuronosyltransferase 1A8 increases the glucuronidation of Sulindac. [27]
Capsaicin DMGMF6V Approved UDP-glucuronosyltransferase 1A8 increases the glucuronidation of Capsaicin. [22]
Ibuprofen DM8VCBE Approved UDP-glucuronosyltransferase 1A8 increases the glucuronidation of Ibuprofen. [21]
Ursodeoxycholic acid DMCUT21 Approved UDP-glucuronosyltransferase 1A8 increases the glucuronidation of Ursodeoxycholic acid. [28]
Estrone DM5T6US Approved UDP-glucuronosyltransferase 1A8 increases the glucuronidation of Estrone. [21]
Morphine DMRMS0L Approved UDP-glucuronosyltransferase 1A8 increases the glucuronidation of Morphine. [29]
Estriol DMOEM2I Approved UDP-glucuronosyltransferase 1A8 increases the glucuronidation of Estriol. [21]
Masoprocol DMMVNZ0 Approved UDP-glucuronosyltransferase 1A8 increases the glucuronidation of Masoprocol. [22]
Flurbiprofen DMGN4BY Approved UDP-glucuronosyltransferase 1A8 increases the glucuronidation of Flurbiprofen. [21]
Mefenamic acid DMK7HFI Approved UDP-glucuronosyltransferase 1A8 increases the glucuronidation of Mefenamic acid. [21]
Salicyclic acid DM2F8XZ Approved UDP-glucuronosyltransferase 1A8 increases the glucuronidation of Salicyclic acid. [21]
Furosemide DMMQ8ZG Approved UDP-glucuronosyltransferase 1A8 increases the glucuronidation of Furosemide. [21]
Entacapone DMLBVKQ Approved UDP-glucuronosyltransferase 1A8 increases the glucuronidation of Entacapone. [30]
Fenoprofen DML5VQ0 Approved UDP-glucuronosyltransferase 1A8 increases the glucuronidation of Fenoprofen. [21]
Diflunisal DM7EN8I Approved UDP-glucuronosyltransferase 1A8 increases the glucuronidation of Diflunisal. [21]
Felbinac DMKZEIB Approved UDP-glucuronosyltransferase 1A8 increases the glucuronidation of Felbinac. [21]
Resveratrol DM3RWXL Phase 3 UDP-glucuronosyltransferase 1A8 increases the glucuronidation of Resveratrol. [31]
Curcumin DMQPH29 Phase 3 UDP-glucuronosyltransferase 1A8 increases the glucuronidation of Curcumin. [22]
EXISULIND DMBY56U Phase 3 UDP-glucuronosyltransferase 1A8 increases the glucuronidation of EXISULIND. [27]
Genistein DM0JETC Phase 2/3 UDP-glucuronosyltransferase 1A8 increases the glucuronidation of Genistein. [22]
Benzo(a)pyrene DMN7J43 Phase 1 UDP-glucuronosyltransferase 1A8 increases the glucuronidation of Benzo(a)pyrene. [22]
Eugenol DM7US1H Patented UDP-glucuronosyltransferase 1A8 increases the glucuronidation of Eugenol. [22]
T83193 DMHO29Y Patented UDP-glucuronosyltransferase 1A8 increases the glucuronidation of T83193. [21]
Steroid derivative 1 DMB0NVQ Patented UDP-glucuronosyltransferase 1A8 increases the glucuronidation of Steroid derivative 1. [21]
Ferulic Acid DMJC7NF Patented UDP-glucuronosyltransferase 1A8 increases the glucuronidation of Ferulic Acid. [21]
INDOPROFEN DM5QSKN Withdrawn from market UDP-glucuronosyltransferase 1A8 increases the glucuronidation of INDOPROFEN. [21]
EMODIN DMAEDQG Terminated UDP-glucuronosyltransferase 1A8 increases the glucuronidation of EMODIN. [22]
Coumestrol DM40TBU Investigative UDP-glucuronosyltransferase 1A8 increases the glucuronidation of Coumestrol. [22]
Chrysin DM7V2LG Investigative UDP-glucuronosyltransferase 1A8 increases the glucuronidation of Chrysin. [22]
Kaempferol DMHEMUB Investigative UDP-glucuronosyltransferase 1A8 increases the glucuronidation of Kaempferol. [22]
Daidzein DMRFTJX Investigative UDP-glucuronosyltransferase 1A8 increases the glucuronidation of Daidzein. [22]
Apigenin DMI3491 Investigative UDP-glucuronosyltransferase 1A8 increases the glucuronidation of Apigenin. [22]
biochanin A DM0HPWY Investigative UDP-glucuronosyltransferase 1A8 increases the glucuronidation of biochanin A. [22]
3,7,3',4'-TETRAHYDROXYFLAVONE DMES906 Investigative UDP-glucuronosyltransferase 1A8 increases the glucuronidation of 3,7,3',4'-TETRAHYDROXYFLAVONE. [22]
Morin DM2OGZ5 Investigative UDP-glucuronosyltransferase 1A8 increases the glucuronidation of Morin. [22]
methyl salicylate DMKCG8H Investigative UDP-glucuronosyltransferase 1A8 increases the glucuronidation of methyl salicylate. [21]
Plumbagin DM9BS50 Investigative UDP-glucuronosyltransferase 1A8 increases the glucuronidation of Plumbagin. [22]
Formononetin DM7WFZ8 Investigative UDP-glucuronosyltransferase 1A8 increases the glucuronidation of Formononetin. [22]
Mononitrophenol DM4QO9G Investigative UDP-glucuronosyltransferase 1A8 increases the glucuronidation of Mononitrophenol. [30]
2-hydroxy-17beta-estradiol DMM9Z0B Investigative UDP-glucuronosyltransferase 1A8 increases the glucuronidation of 2-hydroxy-17beta-estradiol. [21]
Fibrates DMFNTMY Investigative UDP-glucuronosyltransferase 1A8 increases the glucuronidation of Fibrates. [21]
Cinnamic acid DM340FH Investigative UDP-glucuronosyltransferase 1A8 increases the glucuronidation of Cinnamic acid. [21]
ACMC-1AKLT DMRQ70X Investigative UDP-glucuronosyltransferase 1A8 increases the glucuronidation of ACMC-1AKLT. [33]
Hydroxyestrone DMBO7ZD Investigative UDP-glucuronosyltransferase 1A8 increases the glucuronidation of Hydroxyestrone. [21]
BRN-1999480 DMC9Q4D Investigative UDP-glucuronosyltransferase 1A8 increases the glucuronidation of BRN-1999480. [21]
Anthraflavic acid DMN1YFU Investigative UDP-glucuronosyltransferase 1A8 increases the glucuronidation of Anthraflavic acid. [22]
SCOPOLETIN DM645FP Investigative UDP-glucuronosyltransferase 1A8 increases the glucuronidation of SCOPOLETIN. [30]
Quinizarin DMRQCK3 Investigative UDP-glucuronosyltransferase 1A8 increases the glucuronidation of Quinizarin. [22]
Diphenylacetic Acid DMP6IHR Investigative UDP-glucuronosyltransferase 1A8 increases the glucuronidation of Diphenylacetic Acid. [21]
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⏷ Show the Full List of 59 Drug(s)
This DOT Affected the Regulation of Drug Effects of 1 Drug(s)
Drug Name Drug ID Highest Status Interaction REF
Puerarin DMJIMXH Phase 2 UDP-glucuronosyltransferase 1A8 increases the metabolism of Puerarin. [32]
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27 Drug(s) Affected the Gene/Protein Processing of This DOT
Drug Name Drug ID Highest Status Interaction REF
Arsenic DMTL2Y1 Approved Arsenic increases the expression of UDP-glucuronosyltransferase 1A8. [1]
Vorinostat DMWMPD4 Approved Vorinostat decreases the expression of UDP-glucuronosyltransferase 1A8. [2]
Methotrexate DM2TEOL Approved Methotrexate decreases the expression of UDP-glucuronosyltransferase 1A8. [3]
Chenodiol DMQ8JIK Approved Chenodiol increases the expression of UDP-glucuronosyltransferase 1A8. [4]
Propofol DMB4OLE Approved Propofol decreases the activity of UDP-glucuronosyltransferase 1A8. [5]
Omeprazole DM471KJ Approved Omeprazole increases the expression of UDP-glucuronosyltransferase 1A8. [6]
Osimertinib DMRJLAT Approved Osimertinib decreases the activity of UDP-glucuronosyltransferase 1A8. [7]
Doxycycline DM7ICNU Approved Doxycycline increases the expression of UDP-glucuronosyltransferase 1A8. [8]
Tucatinib DMBESUA Approved Tucatinib decreases the activity of UDP-glucuronosyltransferase 1A8. [9]
Opicapone DM1BKA6 Approved Opicapone decreases the activity of UDP-glucuronosyltransferase 1A8. [10]
Canagliflozin DMFRM1I Approved Canagliflozin decreases the activity of UDP-glucuronosyltransferase 1A8. [11]
3,4-Dihydroxycinnamic Acid DMVZL26 Phase 4 3,4-Dihydroxycinnamic Acid decreases the activity of UDP-glucuronosyltransferase 1A8. [12]
BAICALEIN DM4C7E6 Phase 2 BAICALEIN decreases the activity of UDP-glucuronosyltransferase 1A8. [11]
LM-94 DMW3QGJ Phase 1/2 LM-94 increases the activity of UDP-glucuronosyltransferase 1A8. [13]
(+)-JQ1 DM1CZSJ Phase 1 (+)-JQ1 decreases the expression of UDP-glucuronosyltransferase 1A8. [14]
Bisphenol A DM2ZLD7 Investigative Bisphenol A decreases the expression of UDP-glucuronosyltransferase 1A8. [15]
CATECHIN DMY38SB Investigative CATECHIN decreases the activity of UDP-glucuronosyltransferase 1A8. [12]
(E)-4-(3,5-dimethoxystyryl)phenol DMYXI2V Investigative (E)-4-(3,5-dimethoxystyryl)phenol decreases the activity of UDP-glucuronosyltransferase 1A8. [16]
Chlorogenic acid DM2Y3P4 Investigative Chlorogenic acid decreases the activity of UDP-glucuronosyltransferase 1A8. [12]
Piceatannol DMYOP45 Investigative Piceatannol decreases the activity of UDP-glucuronosyltransferase 1A8. [17]
Galangin DM5TQ2O Investigative Galangin decreases the activity of UDP-glucuronosyltransferase 1A8. [18]
Wogonin DMGCF51 Investigative Wogonin decreases the activity of UDP-glucuronosyltransferase 1A8. [11]
P-Coumaric Acid DMGJSVD Investigative P-Coumaric Acid decreases the activity of UDP-glucuronosyltransferase 1A8. [12]
Phloretin DMYA50U Investigative Phloretin decreases the activity of UDP-glucuronosyltransferase 1A8. [12]
AMENTOFLAVONE DMLRNV2 Investigative AMENTOFLAVONE decreases the activity of UDP-glucuronosyltransferase 1A8. [19]
pregnenolone-16alpha-carbonitrile DM0LW7G Investigative pregnenolone-16alpha-carbonitrile increases the expression of UDP-glucuronosyltransferase 1A8. [20]
Phlorizin DMNARGO Investigative Phlorizin decreases the activity of UDP-glucuronosyltransferase 1A8. [12]
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⏷ Show the Full List of 27 Drug(s)

References

1 Arsenic alters transcriptional responses to Pseudomonas aeruginosa infection and decreases antimicrobial defense of human airway epithelial cells. Toxicol Appl Pharmacol. 2017 Sep 15;331:154-163.
2 Gene microarray analysis of human renal cell carcinoma: the effects of HDAC inhibition and retinoid treatment. Cancer Biol Ther. 2008 Oct;7(10):1607-18.
3 UDP-glucuronosyltransferase 1A6 overexpression in breast cancer cells resistant to methotrexate. Biochem Pharmacol. 2011 Jan 1;81(1):60-70.
4 Chenodeoxycholic acid significantly impacts the expression of miRNAs and genes involved in lipid, bile acid and drug metabolism in human hepatocytes. Life Sci. 2016 Jul 1;156:47-56.
5 Effects of beta-estradiol and propofol on the 4-methylumbelliferone glucuronidation in recombinant human UGT isozymes 1A1, 1A8 and 1A9. Biopharm Drug Dispos. 2004 Nov;25(8):339-44.
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 In vitro inhibition of human UDP-glucuronosyltransferase (UGT) 1A1 by osimertinib, and prediction of in vivo drug-drug interactions. Toxicol Lett. 2021 Sep 15;348:10-17. doi: 10.1016/j.toxlet.2021.05.004. Epub 2021 May 24.
8 Aryl hydrocarbon receptor protects lung adenocarcinoma cells against cigarette sidestream smoke particulates-induced oxidative stress. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):293-301.
9 Drug-drug interaction potentials of tucatinib inhibition of human UDP-glucuronosyltransferases. Chem Biol Interact. 2023 Aug 25;381:110574. doi: 10.1016/j.cbi.2023.110574. Epub 2023 May 30.
10 In vitro effects of opicapone on activity of human UDP-glucuronosyltransferases isoforms. Toxicol Lett. 2022 Aug 15;367:3-8. doi: 10.1016/j.toxlet.2022.07.003. Epub 2022 Jul 8.
11 Evaluation of inhibitors of intestinal UDP-glucuronosyltransferases 1A8 and 1A10 using raloxifene as a substrate in Caco-2 cells: Studies with four flavonoids of Scutellaria baicalensis. Toxicol In Vitro. 2021 Apr;72:105087. doi: 10.1016/j.tiv.2021.105087. Epub 2021 Jan 10.
12 Phloretin exhibits potential food-drug interactions by inhibiting human UDP-glucuronosyltransferases in vitro. Toxicol In Vitro. 2022 Oct;84:105447. doi: 10.1016/j.tiv.2022.105447. Epub 2022 Jul 19.
13 Assessment of the inhibition potential of Licochalcone A against human UDP-glucuronosyltransferases. Food Chem Toxicol. 2016 Apr;90:112-22.
14 CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
15 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.
16 Pterostilbene supplements carry the risk of drug interaction via inhibition of UDP-glucuronosyltransferases (UGT) 1A9 enzymes. Toxicol Lett. 2020 Mar 1;320:46-51. doi: 10.1016/j.toxlet.2019.12.008. Epub 2019 Dec 5.
17 Piceatannol exhibits potential food-drug interactions through the inhibition of human UDP-glucuronosyltransferase (UGT) in Vitro. Toxicol In Vitro. 2020 Sep;67:104890. doi: 10.1016/j.tiv.2020.104890. Epub 2020 May 22.
18 Potential interactions among myricetin and dietary flavonols through the inhibition of human UDP-glucuronosyltransferase in vitro. Toxicol Lett. 2022 Apr 1;358:40-47. doi: 10.1016/j.toxlet.2022.01.007. Epub 2022 Jan 19.
19 Amentoflavone is a potent broad-spectrum inhibitor of human UDP-glucuronosyltransferases. Chem Biol Interact. 2018 Mar 25;284:48-55.
20 Tissue-specific, inducible, and hormonal control of the human UDP-glucuronosyltransferase-1 (UGT1) locus. J Biol Chem. 2005 Nov 11;280(45):37547-57.
21 Gastrointestinally distributed UDP-glucuronosyltransferase 1A10, which metabolizes estrogens and nonsteroidal anti-inflammatory drugs, depends upon phosphorylation. J Biol Chem. 2004 Jul 2;279(27):28320-9. doi: 10.1074/jbc.M401396200. Epub 2004 Apr 26.
22 Differential and special properties of the major human UGT1-encoded gastrointestinal UDP-glucuronosyltransferases enhance potential to control chemical uptake. J Biol Chem. 2004 Jan 9;279(2):1429-41.
23 Characterization of UDP-glucuronosyltransferases involved in glucuronidation of diethylstilbestrol in human liver and intestine. Chem Res Toxicol. 2012 Dec 17;25(12):2663-9. doi: 10.1021/tx300310k. Epub 2012 Nov 13.
24 UDP-glucuronosyltransferase 1A1 is the principal enzyme responsible for etoposide glucuronidation in human liver and intestinal microsomes: structural characterization of phenolic and alcoholic glucuronides of etoposide and estimation of enzyme kinetics. Drug Metab Dispos. 2007 Mar;35(3):371-80.
25 Differential rates of glucuronidation for 7-ethyl-10-hydroxy-camptothecin (SN-38) lactone and carboxylate in human and rat microsomes and recombinant UDP-glucuronosyltransferase isoforms. Drug Metab Dispos. 2005 Jul;33(7):977-83. doi: 10.1124/dmd.104.003491. Epub 2005 Apr 15.
26 Characterization of the UDP glucuronosyltransferase activity of human liver microsomes genotyped for the UGT1A1*28 polymorphism. Drug Metab Dispos. 2007 Dec;35(12):2270-80.
27 Glucuronidation of nonsteroidal anti-inflammatory drugs: identifying the enzymes responsible in human liver microsomes. Drug Metab Dispos. 2005 Jul;33(7):1027-35.
28 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.
29 Isoform selectivity and kinetics of morphine 3- and 6-glucuronidation by human udp-glucuronosyltransferases: evidence for atypical glucuronidation kinetics by UGT2B7. Drug Metab Dispos. 2003 Sep;31(9):1086-9. doi: 10.1124/dmd.31.9.1086.
30 Kinetic characterization of the 1A subfamily of recombinant human UDP-glucuronosyltransferases. Drug Metab Dispos. 2005 Jul;33(7):1017-26.
31 Differences in the glucuronidation of resveratrol and pterostilbene: altered enzyme specificity and potential gender differences. Drug Metab Pharmacokinet. 2014;29(2):112-9. doi: 10.2133/dmpk.dmpk-13-rg-012. Epub 2013 Aug 20.
32 UDP-glucuronosyltransferase 1A1 is the principal enzyme responsible for puerarin metabolism in human liver microsomes. Arch Toxicol. 2012 Nov;86(11):1681-90. doi: 10.1007/s00204-012-0874-7. Epub 2012 May 31.
33 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.