22688-79-5Relevant articles and documents
Regioselectivity of phase II metabolism of luteolin and quercetin by UDP-glucuronosyl transferases
Boersma, Marelle G.,Van der Woude, Hester,Bogaards, Jan,Boeren, Sjef,Vervoort, Jacques,Cnubben, Nicole H. P.,Van Iersel, Marlou L. P. S.,Van Bladeren, Peter J.,Rietjens, Ivonne M. C. M.
, p. 662 - 670 (2002)
The regioselectivity of phase II conjugation of flavonoids is expected to be of importance for their biological activity. In the present study, the regioselectivity of phase II biotransformation of the model flavonoids luteolin and quercetin by UDP-glucuronosyltransferases was investigated. Identification of the metabolites formed in microsomal incubations with luteolin or quercetin was done using HPLC, LC-MS, and 1H NMR. The results obtained demonstrate the major sites for glucuronidation to be the 7-, 3-, 3′-, or 4′-hydroxyl moiety. Using these unequivocal identifications, the regioselectivity of the glucuronidation of luteolin and quercetin by microsomal samples from different origin, i.e., rat and human intestine and liver, as well as 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 the isoenzyme of UDP-glucuronosyltransferases (UGT) involved. Human UGTIA1, UGTIA8, and UGTIA9 were shown to be especially active in conjugation of both flavonoids, whereas UGTIA4 and UGTIA10 and the isoenzymes from the UGTB family, UGT2B7 and UGT2B15, were less efficient. Due to the different regioselectivity and activity displayed by the various UDP- glucuronosyltransferases, regioselectivity and rate of flavonoid conjugation varies with species and organ. Qualitative comparison of the regioselectivities of glucuronidation obtained with human intestine and liver microsomes to those obtained with human UGT isoenzymes indicates that, in human liver, especially UGT1A9 and, in intestine, UGT1A1 and UGT1A8 are involved in glucuronidation of quercetin and luteolin. Taking into account the fact that the anti-oxidant action as well as the pro-oxidant toxicity of these catechol-type flavonoids is especially related to their 3′,4′-dihydroxyl moiety, it is of interest to note that the human intestine UGT's appear to be especially effective in conjugating this 3′,4′ catechol unit. This would imply that upon glucuronidation along the transport across the intestinal border, the flavonoids loose a significant part of these biological activities.
Three-dimensional quantitative structure-activity relationship studies on UGT1A9-mediated 3-O-glucuronidation of natural flavonols using a pharmacophore-based comparative molecular field analysis model
Wu, Baojian,Morrow, John Kenneth,Singh, Rashim,Zhang, Shuxing,Hu, Ming
experimental part, p. 403 - 413 (2011/12/16)
Glucuronidation is often recognized as one of the rate-determining factors that limit the bioavailability of flavonols. Hence, design and synthesis of more bioavailable flavonols would benefit from the establishment of predictive models of glucuronidation using kinetic parameters [e.g., Km, V max, intrinsic clearance (CLint) = Vmax/K m] derived for flavonols. This article aims to construct position (3-OH)-specific comparative molecular field analysis (CoMFA) models to describe UDP-glucuronosyltransferase (UGT) 1A9-mediated glucuronidation of flavonols, which can be used to design poor UGT1A9 substrates. The kinetics of recombinant UGT1A9-mediated 3-O-glucuronidation of 30 flavonols was characterized, and kinetic parameters (Km, Vmax, CLint) were obtained. The observed Km, Vmax, and CLint values of 3-O-glucuronidation ranged from 0.04 to 0.68 μM, 0.04 to 12.95 nmol/mg/min, and 0.06 to 109.60 ml/mg/min, respectively. To model UGT1A9-mediated glucuronidation, 30 flavonols were split into the training (23 compounds) and test (7 compounds) sets. These flavonols were then aligned by mapping the flavonols to specific common feature pharmacophores, which were used to construct CoMFA models of Vmax and CLint, respectively. The derived CoMFA models possessed good internal and external consistency and showed statistical significance and substantive predictive abilities (Vmax model: q2 = 0.738, r2 = 0.976, rpred2 = 0.735; CLint model: q2 = 0.561, r2 = 0.938, rpred2 = 0.630). The contour maps derived from CoMFA modeling clearly indicate structural characteristics associated with rapid or slow 3-O-glucuronidation. In conclusion, the approach of coupling CoMFA analysis with a pharmacophore-based structural alignment is viable for constructing a predictive model for regiospecific glucuronidation rates of flavonols by UGT1A9. Copyright
Regiospecific synthesis of quercetin O-β-d-glucosylated and O-β-d-glucuronidated isomers
Kajjout, Mohammed,Rolando, Christian
, p. 4731 - 4741 (2011/07/08)
Quercetin, the polyphenolic compound, which has the highest daily intake, is well known for its protective effects against aging diseases and has received a lot of attention for this reason. Both quercetin 3-O-β-d-glucuronide and quercetin 3′-O-β-d-glucuronide are human metabolites, which, together with their regioisomers, are required for biological as well as physical chemistry studies. We present here a novel synthetic route based on the sequential and selective protections of the hydroxyl functions of quercetin allowing selective glycosylation, followed by TEMPO-mediated oxidation to the glucuronide. This methodology enabled us to synthesize the five O-β-d-glucosides and four O-β-d-glucuronides of quercetin, including the major human metabolite, quercetin 3-O-β-d-glucuronide.
