Disposition of flavonoids via enteric recycling: enzyme stability affects characterization of prunetin glucuronidation across species, organs, and UGT isoforms.

Disposition of flavonoids via enteric recycling: enzyme stability affects characterization of prunetin glucuronidation across species, organs, and UGT isoforms. Research Abstract Details 

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Disposition of flavonoids via enteric recycling: enzyme stability affects characterization of prunetin glucuronidation across species, organs, and UGT isoforms. Abstract Text:

Tiby B Joseph,Stephen W J Wang,Xing Liu,Kaustubh H Kulkarni,Jingrong Wang,Haiyan Xu,Ming Hu,Tiby B Joseph,Stephen W J Wang,Xing Liu,Kaustubh H Kulkarni,Jingrong Wang,Haiyan Xu,Ming Hu,Tiby B Joseph,Stephen W J Wang,Xing Liu,Kaustubh H Kulkarni,Jingrong Wang,Haiyan Xu,Ming Hu,

We characterized the in vitro glucuronidation of prunetin, a prodrug of genistein that is a highly active cancer prevention agent. Metabolism studies were conducted using expressed human UGT isoforms and microsomes/S9 fractions prepared from intestine and liver of rodents and humans. The results indicated that human intestinal microsomes were more efficient than liver microsomes in glucuronidating prunetin, but rates of metabolism were dependent on time of incubation at 37 degrees C. Human liver and intestinal microsomes mainly produced metabolite 1 (prunetin-5- O-glucuronide) and metabolite 2 (prunetin-4'- O-glucuronide), respectively. Using 12 human UGT isoforms, we showed that UGT1A7, UGT1A8, and UGT1A9 were mainly responsible for the formation of metabolite 1, whereas UGT1A1, UGT1A8, and UGT1A10 were mainly responsible for the formation of metabolite 2. This isoform-specific metabolism was consistent with earlier results obtained using human liver and intestinal microsomes, as the former (liver) is UGT1A9-rich whereas the latter is UGT1A10-rich. Surprisingly, we found that the thermostability of the microsomes was isoform- and organ-dependent. For example, human liver microsomal UGT activities were much more heat-stable (37 degrees C) than intestinal microsomal UGT activities, consistent with the finding that human UGT1A9 is much more thermostable than human UGT1A10 and UGT1A8. The organ-specific thermostability profiles were also evident in rat microsomes and mouse S9 fractions, even though human intestinal glucuronidation of prunetin differs significantly from rodent intestinal glucuronidation. In conclusion, prunetin glucuronidation is species-, organ-, and UGT-isoform-dependent, all of which may be impacted by the thermostability of specific UGT isoforms involved in the metabolism.

Disposition of flavonoids via enteric recycling: enzyme stability affects characterization of prunetin glucuronidation across species, organs, and UGT isoforms. Publishing Authors By Initials

TB Joseph,SW Wang,X Liu,KH Kulkarni,J Wang,H Xu,M Hu,TB Joseph,SW Wang,X Liu,KH Kulkarni,J Wang,H Xu,M Hu,TB Joseph,SW Wang,X Liu,KH Kulkarni,J Wang,H Xu,M Hu,

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Disposition of flavonoids via enteric recycling: enzyme stability affects characterization of prunetin glucuronidation across species, organs, and UGT isoforms. Journal Published:

PUBLICATION TYPE: Research Support, Non-U.S. Gov

Journal: Molecular pharmaceutics

VOLUME: 4

Page Numbers: 883-94

Journal Abbreviation: Mol. Pharm.

ISSN: 1543-8384

DAY: 6

MONTH: 12

YEAR: 2007

Disposition of flavonoids via enteric recycling: enzyme stability affects characterization of prunetin glucuronidation across species, organs, and UGT isoforms. Information

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LANGUAGE: eng

NlmUniqueID: 101197791

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Grant and Affiliation Information for Disposition of flavonoids via enteric recycling: enzyme stability affects characterization of prunetin glucuronidation across species, organs, and UGT isoforms.

AFFILIATION: Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, 1441 Moursund Street, Houston, Texas 77030, USA.

Country: United States

AGENCY: United States NIGMS

GRANT: GM70737

ACRONYM: GM

MEDLINETA: Mol Pharm

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