Phase II Metabolism of Hesperetin by Individual UDP-Glucuronosyltransferases and Sulfotransferases and Rat and Human Tissue Samples

Phase II metabolism by UDP-glucuronosyltransferases (UGTs) and sulfotransferases (SULTs) is the predominant metabolic pathway during the first-pass metabolism of hesperetin (4'-methoxy-3',5,7-trihydroxyflavanone). In the present study, we have determined the kinetics for glucuronidation an...

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Published in:	Drug metabolism and disposition Vol. 38; no. 4; pp. 617 - 625
Main Authors:	BRAND, Walter, BOERSMA, Marelle G, RIETJENS, Ivonne M. C. M, BIK, Hanneke, HOEK-VAN DEN HIL, Elisabeth F, VERVOORT, Jacques, BARRON, Denis, MEINL, Walter, GLATT, Hansruedi, WILLIAMSON, Gary, VAN BLADEREN, Peter J
Format:	Journal Article
Language:	English
Published:	Bethesda, MD American Society for Pharmacology and Experimental Therapeutics 01-04-2010
Subjects:	Animals bioavailability Biological and medical sciences Biotransformation caco-2 cell monolayers Cell Line Chromatography, High Pressure Liquid Colon - metabolism conjugated metabolites Cytosol - enzymology Cytosol - metabolism DNA, Complementary - biosynthesis DNA, Complementary - genetics expression flavanones gastrointestinal-tract Glucosides - metabolism Glucuronosyltransferase - metabolism Hesperidin - pharmacokinetics Humans identification In Vitro Techniques Insecta Intestine, Small - metabolism Kinetics Liver - metabolism Magnetic Resonance Spectroscopy Male Medical sciences messenger-rna Microsomes, Liver - enzymology Microsomes, Liver - metabolism orange juice Pharmacology. Drug treatments Rats Rats, Sprague-Dawley Sulfates - metabolism Sulfotransferases - metabolism tc7 cells Transfection Human Sulfotransferases Rat UDP-glucuronosyltransferase Enzyme Transferases Glycosyltransferases Rodentia Metabolism Vertebrata Mammalia Animal Hexosyltransferases Pharmacokinetics
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Summary:	Phase II metabolism by UDP-glucuronosyltransferases (UGTs) and sulfotransferases (SULTs) is the predominant metabolic pathway during the first-pass metabolism of hesperetin (4'-methoxy-3',5,7-trihydroxyflavanone). In the present study, we have determined the kinetics for glucuronidation and sulfonation of hesperetin by 12 individual UGT and 12 individual SULT enzymes as well as by human or rat small intestinal, colonic, and hepatic microsomal and cytosolic fractions. Results demonstrate that hesperetin is conjugated at positions 7 and 3' and that major enzyme-specific differences in kinetics and regioselectivity for the UGT and SULT catalyzed conjugations exist. UGT1A9, UGT1A1, UGT1A7, UGT1A8, and UGT1A3 are the major enzymes catalyzing hesperetin glucuronidation, the latter only producing 7-O-glucuronide, whereas UGT1A7 produced mainly 3'-O-glucuronide. Furthermore, UGT1A6 and UGT2B4 only produce hesperetin 7-O-glucuronide, whereas UGT1A1, UGT1A8, UGT1A9, UGT1A10, UGT2B7, and UGT2B15 conjugate both positions. SULT1A2 and SULT1A1 catalyze preferably and most efficiently the formation of hesperetin 3'-O-sulfate, and SULT1C4 catalyzes preferably and most efficiently the formation of hesperetin 7-O-sulfate. Based on expression levels SULT1A3 and SULT1B1 also will probably play a role in the sulfo-conjugation of hesperetin in vivo. The results help to explain discrepancies in metabolite patterns determined in tissues or systems with different expression of UGTs and SULTs, e.g., hepatic and intestinal fractions or Caco-2 cells. The incubations with rat and human tissue samples support an important role for intestinal cells during first-pass metabolism in the formation of hesperetin 3'-O-glucuronide and 7-O-glucuronide, which appear to be the major hesperetin metabolites found in vivo.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0090-9556 1521-009X
DOI:	10.1124/dmd.109.031047