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Mouse UDP‐glucuronosyltransferase Enzymes Capable of Metabolizing Toxic Estrogen Derivatives: Serine Residues Play Crucial Role to Substrate Turnover.
Author(s) -
RAYCHOUDHURI AMIT,
JANA SIRSENDU,
BASU MOUSUMI,
BASU NIKHIL K,
OWENS IDA S
Publication year - 2013
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.27.1_supplement.791.3
Subject(s) - enzyme , glucuronidation , isozyme , diethylstilbestrol , biochemistry , serine , metabolism , drug metabolism , chemistry , gene isoform , estrogen , biology , microsome , gene , hormone , genetics
A comprehensive study of mouse UGT isoforms Ugt2b34 and Ugt2b36 was carried in COS‐1 cells in order to understand differences and the significance of apparent adaptations between mouse and human isozymes. Understanding the mouse UGT versus human drug metabolizing enzymes will contribute significant knowledge about our physiology/biochemistry and habitat driven by evolutionary mechanism of dug metabolism. Our study by q‐RT PCR unexpectedly revealed the prostate distribution of these isozymes apart from mouse liver. Glucuronidation assay showed that both Ugt2b34 and Ugt2b36 possess genotoxic 4‐OH estrogen metabolism ability, with Ugt2b36 being far higher turnover number. Ugt2b34 has more substrate range; it is far more effective in metabolizing phyto‐estrogens and phytochemicals. These two enzymes are also effective in metabolizing xenoestrogens like bisphenol A (BPA) and diethylstilbestrol (DES). We also found by site directed mutagenesis that serine‐174 in Ugt2b34 and ser‐172 in Ugt2b36 is essential for the enzymatic activity. Further studies showed that Ugt2b34 is readily inhibited by kinase inhibitors, while, Ugt2b36 is a robust enzyme which is not susceptible to inhibition. This work was supported, in whole or in part, by the NICHD Intramural Research Program.