Min Zeng1,2, Rongjin Sun3,2,4,5, Sumit Basu2, Yong Ma2, Shufan Ge2, Taijun Yin2, Song Gao2, Jun Zhang1, Ming Hu3,2. 1. Department of Thoracic and Cardiomacrovascular Surgery, Hubei University of Medicine Affiliated Shiyan Taihe Hospital, Shiyan, Hubei, China. 2. Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX, USA. 3. College of Pharmacy, Hubei University of Medicine, Shiyan, Hubei, China. 4. Hubei Provincial Technology and Research Center for Comprehensive Development of Medicinal Herbs, Hubei University of Medicine, Shiyan, Hubei, China. 5. Hubei Key Laboratory of Wudang Local Chinese Medicine Research, Hubei University of Medicine, Shiyan, Hubei, China.
Abstract
SCOPE: Enterohepatic recycling is often thought to involve mostly phase II metabolites generated in the liver. This study aims to determine if direct biliary excretion of extrahepatically generated glucuronides would also enable recycling. METHODS AND RESULTS: Conventional and modified intestinal perfusion models along with intestinal and liver microsomes were used to determine the contribution of extrahepatically derived glucuronides. Glucuronidation of four flavonoids (genistein, biochanin A, apigenin, and chrysin at 2.5-20 μM) were generally more rapid in the hepatic than intestinal microsomes. Furthermore, when aglycones (at 10 μM each) were perfused, larger (1.7-9 fold) amounts of glucuronides were found in the bile than in the luminal perfusate. However, higher concentrations of glucuronides were not found in jugular vein than portal vein, and apigenin glucuronide actually displayed a significantly lower concentration in jugular vein (<1 nM) than portal vein (≈4 nM). A direct portal infusion of four flavonoid glucuronides (5.9-10.4 μM perfused at 2 mL/h) showed that the vast majority (>65%) of the glucuronides (except for biochanin A glucuronide) administered were efficiently excreted into the bile. CONCLUSION: Direct biliary excretion of extrahepatically generated flavonoid glucuronides is a highly efficient clearance mechanism, which should enable enterohepatic recycling of flavonoids without hepatic conjugating enzymes.
SCOPE: Enterohepatic recycling is often thought to involve mostly phase II metabolites generated in the liver. This study aims to determine if direct biliary excretion of extrahepatically generated glucuronides would also enable recycling. METHODS AND RESULTS: Conventional and modified intestinal perfusion models along with intestinal and liver microsomes were used to determine the contribution of extrahepatically derived glucuronides. Glucuronidation of four flavonoids (genistein, biochanin A, apigenin, and chrysin at 2.5-20 μM) were generally more rapid in the hepatic than intestinal microsomes. Furthermore, when aglycones (at 10 μM each) were perfused, larger (1.7-9 fold) amounts of glucuronides were found in the bile than in the luminal perfusate. However, higher concentrations of glucuronides were not found in jugular vein than portal vein, and apigenin glucuronide actually displayed a significantly lower concentration in jugular vein (<1 nM) than portal vein (≈4 nM). A direct portal infusion of four flavonoid glucuronides (5.9-10.4 μM perfused at 2 mL/h) showed that the vast majority (>65%) of the glucuronides (except for biochanin Aglucuronide) administered were efficiently excreted into the bile. CONCLUSION: Direct biliary excretion of extrahepatically generated flavonoid glucuronides is a highly efficient clearance mechanism, which should enable enterohepatic recycling of flavonoids without hepatic conjugating enzymes.
Authors: Stefan Oswald; Jörg König; Dieter Lütjohann; Thomas Giessmann; Heyo K Kroemer; Christian Rimmbach; Dieter Rosskopf; Martin F Fromm; Werner Siegmund Journal: Pharmacogenet Genomics Date: 2008-07 Impact factor: 2.089
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