Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTL98JZE)

• DOT Name: UDP-glucuronosyltransferase 2A1
• Synonyms: UDPGT 2A1; UGT2A1; EC 2.4.1.17
• Gene Name: UGT2A1
• UniProt ID: UD2A1_HUMAN
• EC Number: 2.4.1.17
• Pfam ID: PF00201
• Sequence:
  MLNNLLLFSLQISLIGTTLGGNVLIWPMEGSHWLNVKIIIDELIKKEHNVTVLVASGALF
  ITPTSNPSLTFEIYKVPFGKERIEGVIKDFVLTWLENRPSPSTIWRFYQEMAKVIKDFHM
  VSQEICDGVLKNQQLMAKLKKSKFEVLVSDPVFPCGDIVALKLGIPFMYSLRFSPASTVE
  KHCGKVPYPPSYVPAVLSELTDQMSFTDRIRNFISYHLQDYMFETLWKSWDSYYSKALGG
  LLLCCPGWSAVADLGSLQPLLPGFKRFSRLSLHCSWDYRLPAGRPTTLCETMGKAEIWLI
  RTYWDFEFPRPYLPNFEFVGGLHCKPAKPLPKVLWRYKGKKPATLGNNTQLFDWIPQNDL
  LGHPKTKAFITHGGTNGIYEAIYHGVPMVGVPMFADQPDNIAHMKAKGAAVEVNLNTMTS
  VDLLSALRTVINEPSYKENAMRLSRIHHDQPVKPLDRAVFWIEFVMRHKGAKHLRVAAHD
  LTWFQYHSLDVIGFLLVCVTTAIFLVIQCCLFSCQKFGKIGKKKKRE
• 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. Essential for the elimination and detoxification of drugs, xenobiotics and endogenous compounds. Catalyzes the glucuronidation of endogenous steroid hormones such as androgens (testosterone and epitestosterone) and estrogens (estradiol and epiestriol). Contributes to bile acid (BA) detoxification by catalyzing the glucuronidation of BA substrates, which are natural detergents for dietary lipids absorption. Shows a high affinity to aliphatic odorants such as citronellol as well as olfactory tissue specificity, and therefore may be involved in olfaction. Shows a potential role in detoxification of toxic waste compounds in the amniotic fluid before birth, and air-born chemical after birth.
• Tissue Specificity: Olfactory epithelium, brain and fetal lung . Not present in liver .
• 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)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Biotransformations of 5 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Indomethacin	DMSC4A7	Approved	UDP-glucuronosyltransferase 2A1 increases the glucuronidation of Indomethacin.	[4]
LM-94	DMW3QGJ	Phase 1/2	UDP-glucuronosyltransferase 2A1 increases the glucuronidation of LM-94.	[5]
Bisphenol A	DM2ZLD7	Investigative	UDP-glucuronosyltransferase 2A1 increases the glucuronidation of Bisphenol A.	[6]
Hydroxybenzo(a)pyrene	DM9H5EN	Investigative	UDP-glucuronosyltransferase 2A1 increases the glucuronidation of Hydroxybenzo(a)pyrene.	[5]
Hydroxybenzo[a]pyrene	DMFSKYE	Investigative	UDP-glucuronosyltransferase 2A1 increases the glucuronidation of Hydroxybenzo[a]pyrene.	[5]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Aminohippuric acid	DMUN54G	Investigative	UDP-glucuronosyltransferase 2A1 affects the response to substance of Aminohippuric acid.	[5]

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 UDP-glucuronosyltransferase 2A1.	[1]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of UDP-glucuronosyltransferase 2A1.	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of UDP-glucuronosyltransferase 2A1.	[2]

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] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [3] 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.
• [4] Highly variable pH effects on the interaction of diclofenac and indomethacin with human UDP-glucuronosyltransferases. Toxicol In Vitro. 2012 Dec;26(8):1286-93. doi: 10.1016/j.tiv.2012.01.005. Epub 2012 Jan 14.
• [5] Characterization of UDP-glucuronosyltransferase 2A1 (UGT2A1) variants and their potential role in tobacco carcinogenesis. Pharmacogenet Genomics. 2011 Feb;21(2):55-65. doi: 10.1097/FPC.0b013e328341db05.
• [6] Differences in the glucuronidation of bisphenols F and S between two homologous human UGT enzymes, 1A9 and 1A10. Xenobiotica. 2015;45(6):511-9. doi: 10.3109/00498254.2014.999140. Epub 2014 Dec 30.