کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
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2496329 | 1116122 | 2016 | 10 صفحه PDF | دانلود رایگان |
![عکس صفحه اول مقاله: Wedelolactone metabolism in rats through regioselective glucuronidation catalyzed by uridine diphosphate-glucuronosyltransferases 1As (UGT1As) Wedelolactone metabolism in rats through regioselective glucuronidation catalyzed by uridine diphosphate-glucuronosyltransferases 1As (UGT1As)](/preview/png/2496329.png)
BackgroundWedelolactone (WEL), a medicinal plant-derived coumestan, has been reported to exhibit a diverse range of pharmacological activities. However, the metabolism and disposition of WEL remain unexplored.PurposeThe present study aims to investigate the metabolism of WEL in rats and identify the enzymes responsible for forming major WEL metabolites.MethodsPlasma, urine, feces, and bile samples were collected before and after 50 mg/kg WEL was orally administered to rats. Metabolites were profiled by ultrahigh performance liquid chromatography/quadrupole time-of-flight mass spectrometry and identified by high-performance liquid chromatography-solid-phase extraction-nuclear magnetic resonance spectroscopy. The in vitro WEL glucuronidation activities of human liver microsomes, human kidney microsomes, human intestine microsomes, and 12 recombinant human uridine diphosphate-glucuronosyltransferase (UGT) isoforms were screened. Molecular docking simulation of the interaction between WEL and UGT1A9 was conducted.ResultsWEL underwent extensive metabolism, and 17 metabolites were identified. The major metabolic pathways observed were glucuronidation and methylation. Glucuronic acid was preferentially introduced into 5-OH, whereas no obvious regioselectivity was observed in the methylation of 11-OH and 12-OH. Multiple UGTs, including UGT1A1, UGT1A3, UGT1A6, UGT1A7, UGT1A8, UGT1A9, and UGT1A10, were involved in forming WEL glucuronides and O-methylated WEL glucuronides.ConclusionThe extensive glucuronidation and methylation is responsible for the low oral bioavailability of WEL in rats. UGT1A1 and UGT1A9 were the major enzymes involved in the glucuronidation of WEL and O-methylated WEL. Molecular docking studies revealed that 5-OH was accessible to the catalytic domain of UGT1As; therefore, 5-OH exhibited a high probability of glucuronidation.
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Journal: Phytomedicine - Volume 23, Issue 4, 15 April 2016, Pages 340–349