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• W2158528062 endingPage "1639" @default.
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• W2158528062 abstract "Mycophenolic acid (MPA) is the active immunosuppressive metabolite of the anti-organ rejection drug mycophenolate mofetil (MMF) and is implicated in the gastrointestinal toxicity associated with MMF therapy. Intestinal UDP-glucuronosyltransferases (UGT) have been proposed to provide intrinsic resistance against MMF-induced gastrointestinal toxicity by converting MPA to the inactive MPA 7-<i>O</i>-glucuronide. Using an optimized intestinal microsome preparation method that stabilized the intestinal MPA UGT activity, the MPA UGT activity of male Sprague-Dawley rat intestinal microsomes was characterized. A longitudinal gradient similar to that described for other phenolic compounds was observed, with the activity decreasing from the duodenum to the distal small intestine and colon. The catalytic efficiency of MPA glucuronidation decreased from the proximal to distal intestine as a result of decreasing <i>V</i>_max and increasing <i>K</i>_m. The finding that homozygous Gunn rats lack detectable intestinal MPA UGT activity indicates exclusive roles of UGT1A1, UGT1A6, and/or UGT1A7. Quantitative immunoblotting revealed a parallel between the MPA UGT activity and the content of UGT1A7-like immunoreactivity (18.7 and 7.3 μg/mg for duodenum and colon, respectively). In contrast, the lesser MPA-metabolizing UGT, UGT1A1 and UGT1A6, were lower in abundance (1.6–2.1 and 1.7–2.9 μg/mg, respectively), and their patterns of longitudinal distribution were distinct from the MPA UGT activity. These data suggest a dominant role of a UGT1A7-like enzyme, presumably UGT1A7 itself, in the catalysis of rat intestinal MPA glucuronidation. Studies are ongoing to investigate the relationship between intestinal UGT1A enzymes and susceptibility to MMF-induced gastrointestinal toxicity." @default.
• W2158528062 created "2016-06-24" @default.
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• W2158528062 date "2006-06-21" @default.
• W2158528062 modified "2023-10-16" @default.
• W2158528062 title "Characterization of Rat Intestinal Microsomal UDP-Glucuronosyltransferase Activity toward Mycophenolic Acid" @default.
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• W2158528062 doi "https://doi.org/10.1124/dmd.106.010140" @default.
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