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The glucuronidation of native and oxidized estrogens can be effectively inhibited by compounds structurally related to UDP‐glucuronic acid in human recombinant UGT1A10
Author(s) -
Mazur Anna,
Bratton Stacie Moseley,
Miller Grover P,
Finel Moshe,
RadominskaPandya Anna
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.23.1_supplement.750.2
Subject(s) - glucuronidation , chemistry , estrogen , glucuronic acid , glucuronosyltransferase , uridine , substrate (aquarium) , mechanism of action , moiety , pharmacology , metabolism , enzyme , non competitive inhibition , biochemistry , stereochemistry , microsome , endocrinology , in vitro , biology , rna , polysaccharide , ecology , gene
Human UGT1A10 glucuronidates physiologically important substrates such as native and hydroxylated estrogens and drugs. Modulation of UGT1A10 activity can alter estrogen metabolism and disposition resulting in alterations of its status in the body. Here, the effect of bi‐dentate inhibitors containing a lipophilic and uridine moiety on UGT1A10 estradiol (E 2 ) and 4‐hydroxyestradiol (4‐OH‐E 2 ) glucuronidation was investigated. Comparisons of detailed inhibition analyses (IC 50 and K i values) for the best inhibitor in the series, PP55B, were made, and for each substrate these data were found not to follow classical inhibition models. Increasing concentrations of PP55B affected the glucuronidation of E 2 and 4‐OH‐E 2 very differently. For E 2 , 2‐25 µM of inhibitor caused an activation of activity (~50%) and followed by a gradual decrease in activity at higher concentrations with 100% inhibition seen at ~600 µM. A multiple binding site model may explain this observation. For 4‐OH‐E 2 , no effect was seen from 2‐25 µM PP55B, followed by a rapid decline in activity was seen with 100% inhibition seen at ~300 µM. This data indicates that UGT1A10 can be effectively inhibited by PP55B. These findings are undergoing further analysis to elucidate the mechanism of action, which could have significant clinical and pharmacological applications for designing UGT inhibitors. NIH‐DK60109, GM075893 (AR‐P)