Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTSVIF4E)

• DOT Name: UDP-glucuronosyltransferase 2B17
• Synonyms: UDPGT 2B17; UGT2B17; EC 2.4.1.17; C19-steroid-specific UDP-glucuronosyltransferase; C19-steroid-specific UDPGT
• Gene Name: UGT2B17
• UniProt ID: UDB17_HUMAN
• PDB ID: 7YAN
• EC Number: 2.4.1.17
• Pfam ID: PF00201
• Sequence:
  MSLKWMSVFLLMQLSCYFSSGSCGKVLVWPTEYSHWINMKTILEELVQRGHEVIVLTSSA
  SILVNASKSSAIKLEVYPTSLTKNDLEDFFMKMFDRWTYSISKNTFWSYFSQLQELCWEY
  SDYNIKLCEDAVLNKKLMRKLQESKFDVLLADAVNPCGELLAELLNIPFLYSLRFSVGYT
  VEKNGGGFLFPPSYVPVVMSELSDQMIFMERIKNMIYMLYFDFWFQAYDLKKWDQFYSEV
  LGRPTTLFETMGKAEMWLIRTYWDFEFPRPFLPNVDFVGGLHCKPAKPLPKEMEEFVQSS
  GENGIVVFSLGSMISNMSEESANMIASALAQIPQKVLWRFDGKKPNTLGSNTRLYKWLPQ
  NDLLGHPKTKAFITHGGTNGIYEAIYHGIPMVGIPLFADQHDNIAHMKAKGAALSVDIRT
  MSSRDLLNALKSVINDPIYKENIMKLSRIHHDQPVKPLDRAVFWIEFVMRHKGAKHLRVA
  AHNLTWIQYHSLDVIAFLLACVATMIFMITKCCLFCFRKLAKTGKKKKRD
• Function: 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. Catalyzes the glucuronidation of endogenous steroid hormones such as androgens (epitestosterone, androsterone) and estrogens (estradiol, epiestradiol).
• Tissue Specificity: Expressed in various tissues including the liver, kidney, testis, uterus, placenta, mammary gland, adrenal gland, skin and prostate.
• 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)
  Prednisone ADME (R-HSA-9757110)
  Glucuronidation (R-HSA-156588)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Biotransformations of 4 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Vorinostat	DMWMPD4	Approved	UDP-glucuronosyltransferase 2B17 increases the glucuronidation of Vorinostat.	[16]
Diclofenac	DMPIHLS	Approved	UDP-glucuronosyltransferase 2B17 increases the glucuronidation of Diclofenac.	[17]
Ursodeoxycholic acid	DMCUT21	Approved	UDP-glucuronosyltransferase 2B17 increases the glucuronidation of Ursodeoxycholic acid.	[18]
BRN-3548355	DM4KXT0	Investigative	UDP-glucuronosyltransferase 2B17 increases the glucuronidation of BRN-3548355.	[20]

This DOT Affected the Regulation of Drug Effects of 3 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Dihydrotestosterone	DM3S8XC	Phase 4	UDP-glucuronosyltransferase 2B17 increases the metabolism of Dihydrotestosterone.	[19]
Androsterone	DMITJAK	Phase 3	UDP-glucuronosyltransferase 2B17 increases the metabolism of Androsterone.	[19]
Eugenol	DM7US1H	Patented	UDP-glucuronosyltransferase 2B17 increases the metabolism of Eugenol.	[19]

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 2B17.	[1]

20 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 UDP-glucuronosyltransferase 2B17.	[2]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of UDP-glucuronosyltransferase 2B17.	[3]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of UDP-glucuronosyltransferase 2B17.	[4]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of UDP-glucuronosyltransferase 2B17.	[5]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of UDP-glucuronosyltransferase 2B17.	[5]
Phenobarbital	DMXZOCG	Approved	Phenobarbital decreases the expression of UDP-glucuronosyltransferase 2B17.	[6]
Bicalutamide	DMZMSPF	Approved	Bicalutamide decreases the expression of UDP-glucuronosyltransferase 2B17.	[7]
Tucatinib	DMBESUA	Approved	Tucatinib decreases the activity of UDP-glucuronosyltransferase 2B17.	[8]
3,4-Dihydroxycinnamic Acid	DMVZL26	Phase 4	3,4-Dihydroxycinnamic Acid decreases the activity of UDP-glucuronosyltransferase 2B17.	[9]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of UDP-glucuronosyltransferase 2B17.	[10]
LM-94	DMW3QGJ	Phase 1/2	LM-94 increases the activity of UDP-glucuronosyltransferase 2B17.	[11]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of UDP-glucuronosyltransferase 2B17.	[12]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of UDP-glucuronosyltransferase 2B17.	[13]
Daidzein	DMRFTJX	Investigative	Daidzein increases the expression of UDP-glucuronosyltransferase 2B17.	[10]
Chlorogenic acid	DM2Y3P4	Investigative	Chlorogenic acid decreases the activity of UDP-glucuronosyltransferase 2B17.	[9]
P-Coumaric Acid	DMGJSVD	Investigative	P-Coumaric Acid decreases the activity of UDP-glucuronosyltransferase 2B17.	[9]
EPZ-004777	DMLN4V5	Investigative	EPZ-004777 increases the expression of UDP-glucuronosyltransferase 2B17.	[14]
Phloretin	DMYA50U	Investigative	Phloretin decreases the activity of UDP-glucuronosyltransferase 2B17.	[9]
AMENTOFLAVONE	DMLRNV2	Investigative	AMENTOFLAVONE decreases the activity of UDP-glucuronosyltransferase 2B17.	[15]
Phlorizin	DMNARGO	Investigative	Phlorizin decreases the activity of UDP-glucuronosyltransferase 2B17.	[9]

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] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [3] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [4] Long-term estrogen exposure promotes carcinogen bioactivation, induces persistent changes in gene expression, and enhances the tumorigenicity of MCF-7 human breast cancer cells. Toxicol Appl Pharmacol. 2009 Nov 1;240(3):355-66.
• [5] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [6] Dose- and time-dependent effects of phenobarbital on gene expression profiling in human hepatoma HepaRG cells. Toxicol Appl Pharmacol. 2009 Feb 1;234(3):345-60.
• [7] Microarray analysis of bicalutamide action on telomerase activity, p53 pathway and viability of prostate carcinoma cell lines. J Pharm Pharmacol. 2005 Jan;57(1):83-92.
• [8] 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.
• [9] 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.
• [10] Molecular signatures of soy-derived phytochemicals in androgen-responsive prostate cancer cells: a comparison study using DNA microarray. Mol Carcinog. 2006 Dec;45(12):943-56.
• [11] Assessment of the inhibition potential of Licochalcone A against human UDP-glucuronosyltransferases. Food Chem Toxicol. 2016 Apr;90:112-22.
• [12] 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.
• [13] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [14] Histone methyltransferase DOT1L coordinates AR and MYC stability in prostate cancer. Nat Commun. 2020 Aug 19;11(1):4153. doi: 10.1038/s41467-020-18013-7.
• [15] Amentoflavone is a potent broad-spectrum inhibitor of human UDP-glucuronosyltransferases. Chem Biol Interact. 2018 Mar 25;284:48-55.
• [16] Warfarin is an effective modifier of multiple UDP-glucuronosyltransferase enzymes: evaluation of its potential to alter the pharmacokinetics of zidovudine. J Pharm Sci. 2015 Jan;104(1):244-56.
• [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] 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.
• [19] Isolation and characterization of a novel cDNA encoding a human UDP-glucuronosyltransferase active on C19 steroids. J Biol Chem. 1996 Sep 13;271(37):22855-62. doi: 10.1074/jbc.271.37.22855.
• [20] Prominent Stereoselectivity of NNAL Glucuronidation in Upper Aerodigestive Tract Tissues. Chem Res Toxicol. 2019 Aug 19;32(8):1689-1698. doi: 10.1021/acs.chemrestox.9b00217. Epub 2019 Jul 30.