Regioselectivity of Phase II Metabolism of Luteolin and Quercetin by UDP-Glucuronosyl Transferases

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• 作者：Marelle G. Boersma ; Hester van der Woude ; Jan Bogaards ; Sjef Boeren ; Jacques Vervoort ; Nicole H. P. Cnubben ; Marlou L. P. S. van Iersel ; Peter J. van Bladeren ; and Ivonne M. C. M. Rietjens
• 刊名：Chemical Research in Toxicology
• 出版年：2002
• 出版时间：May 2002
• 年：2002
• 卷：15
• 期：5
• 页码：662 - 670
• 全文大小：94K
• 年卷期：v.15,no.5(May 2002)
• ISSN：1520-5010

文摘

The regioselectivity of phase II conjugation of flavonoids is expected to be of importance fortheir biological activity. In the present study, the regioselectivity of phase II biotransformationof the model flavonoids luteolin and quercetin by UDP-glucuronosyltransferases was investigated. Identification of the metabolites formed in microsomal incubations with luteolin orquercetin was done using HPLC, LC-MS, and ¹H NMR. The results obtained demonstrate themajor sites for glucuronidation to be the 7-, 3-, 3'-, or 4'-hydroxyl moiety. Using theseunequivocal identifications, the regioselectivity of the glucuronidation of luteolin and quercetinby microsomal samples from different origin, i.e., rat and human intestine and liver, as wellas by various individual human UDP-glucuronosyltransferase isoenzymes was characterized.The results obtained reveal that regioselectivity is dependent on the model flavonoid of interest,glucuronidation of luteolin and quercetin not following the same pattern, depending on theisoenzyme of UDP-glucuronosyltransferases (UGT) involved. Human UGT1A1, UGT1A8, andUGT1A9 were shown to be especially active in conjugation of both flavonoids, whereas UGT1A4and UGT1A10 and the isoenzymes from the UGTB family, UGT2B7 and UGT2B15, were lessefficient. Due to the different regioselectivity and activity displayed by the various UDP-glucuronosyltransferases, regioselectivity and rate of flavonoid conjugation varies with speciesand organ. Qualitative comparison of the regioselectivities of glucuronidation obtained withhuman intestine and liver microsomes to those obtained with human UGT isoenzymes indicatesthat, in human liver, especially UGT1A9 and, in intestine, UGT1A1 and UGT1A8 are involvedin glucuronidation of quercetin and luteolin. Taking into account the fact that the anti-oxidantaction as well as the pro-oxidant toxicity of these catechol-type flavonoids is especially relatedto their 3',4'-dihydroxyl moiety, it is of interest to note that the human intestine UGT's appearto be especially effective in conjugating this 3',4' catechol unit. This would imply that uponglucuronidation along the transport across the intestinal border, the flavonoids loose asignificant part of these biological activities.