RGD Reference Report - The configuration of the 17-hydroxy group variably influences the glucuronidation of beta-estradiol and epiestradiol by human UDP-glucuronosyltransferases. - Rat Genome Database

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The configuration of the 17-hydroxy group variably influences the glucuronidation of beta-estradiol and epiestradiol by human UDP-glucuronosyltransferases.

Authors: Itäaho, Katriina  Mackenzie, Peter I  Ikushiro, Shin-ichi  Miners, John O  Finel, Moshe 
Citation: Itäaho K, etal., Drug Metab Dispos. 2008 Nov;36(11):2307-15. doi: 10.1124/dmd.108.022731. Epub 2008 Aug 21.
RGD ID: 40902964
Pubmed: PMID:18719240   (View Abstract at PubMed)
DOI: DOI:10.1124/dmd.108.022731   (Journal Full-text)

The glucuronidation of 17beta-estradiol (beta-estradiol) and 17alpha-estradiol (epiestradiol) was studied to elucidate how the orientation of the 17-OH group affects conjugation at the 3-OH or the 17-OH of either diastereomer. Recombinant human UDP-glucuronosyltransferases (UGTs) UGT1A1, UGT1A3, UGT1A7, UGT1A8, and UGT1A10 conjugated one or both diastereomers, mainly at the 3-OH. The activity of UGT1A4 was low and unique because it was directed merely toward the 17-OH of both aglycones. UGT1A10 exhibited particularly high estradiol glucuronidation activity, the rate and affinity of which were significantly higher in the case of beta-estradiol than with epiestradiol. UGT1A9 did not catalyze estradiol glucuronidation, but UGT1A9-catalyzed scopoletin glucuronidation was competitively inhibited by beta-estradiol. UGT2B4, UGT2B7, and UGT2B17 exclusively conjugated the estradiols at the 17-OH position in a highly stereoselective fashion. UGT2B4 was specific for epiestradiol; UGT2B7 glucuronidated both diastereomers, with high affinity for epiestradiol, whereas UGT2B17 only glucuronidated beta-estradiol. UGT2B15 glucuronidated both estradiols at the 3-OH, with a strong preference for epiestradiol. Human UGT2A1 and UGT2A2 glucuronidated both diastereoisomers at both hydroxyl groups. Microsomal studies revealed that human liver mainly yielded epiestradiol 17-O-glucuronide, and human intestine primarily yielded beta-estradiol 3-O-glucuronide, whereas rat liver preferentially formed beta-estradiol 17-O-glucuronide. Of the three recombinant rat UGTs that were examined in this study, rUGT2B1 was specific for the 17-OH of beta-estradiol, rUGT2B2 did not catalyze estradiol glucuronidation, whereas rUGT2B3 exhibited high activity toward the 17-OH in both diastereoisomers. The results show that although many UGTs can catalyze estradiol glucuronidation, there are marked differences in their kinetics, regioselectivity, and stereoselectivity.



Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
Ugt2b1Ratcellular glucuronidation involved_inIDA PMID:18719240UniProt 
Ugt2b1Ratestrogen metabolic process involved_inIDA PMID:18719240UniProt 

Molecular Function

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
Ugt2b1Ratglucuronosyltransferase activity enablesIDA PMID:18719240UniProt 

Objects Annotated

Genes (Rattus norvegicus)
Ugt2b1  (UDP glucuronosyltransferase 2 family, polypeptide B1)


Additional Information