NDLI: Regioselective Glucuronidation of Flavonols by Six Human UGT1A Isoforms

Content Provider	Springer Nature Link
Author	Wu, Baojian Xu, Beibei Hu, Ming
Copyright Year	2011
Abstract	Glucuronidation is a major barrier to flavonoid bioavailability; understanding its regiospecificity and reaction kinetics would greatly enhance our ability to model and predict flavonoid disposition. We aimed to determine the regioselective glucuronidation of four model flavonols using six expressed human UGT1A isoforms (UGT1A1, 1A3, 1A7, 1A8, 1A9, 1A10). In vitro reaction kinetic profiles of six UGT1A-mediated metabolism of four flavonols (all with 7-OH group) were characterized; kinetic parameters (K$_{m}$, V$_{max}$ and CL$_{int}$ = V$_{max}$/K$_{m}$) were determined.UGT1A1 and 1A3 regioselectively metabolized the 7-OH group, whereas UGT1A7, 1A8, 1A9 and 1A10 preferred to glucuronidate the 3-OH group. UGT1A1 and 1A9 were the most efficient conjugating enzymes with K$_{m}$ values of ≤1 μM and relative catalytic efficiency ratios of ≥5.5. Glucuronidation by UGT1As displayed surprisingly strong substrate inhibition. In particular, K$_{si}$ values (substrate inhibition constant) were less than 5.4 μM for UGT1A1-mediated metabolism.UGT1A isoforms displayed distinct positional preferences between 3-OH and 7-OH of flavonols. Differentiated kinetic properties between 3-O- and 7-O- glucuronidation suggested that (at least) two distinct binding modes within the catalytic domain were possible. The existence of multiple binding modes should provide better “expert” knowledge to model and predict UGT1A-mediated glucuronidation.
Starting Page	1905
Ending Page	1918
Page Count	14
File Format	PDF
ISSN	07248741
Journal	Pharmaceutical Research
Volume Number	28
Issue Number	8
e-ISSN	1573904X
Language	English
Publisher	Springer US
Publisher Date	2011-04-07
Publisher Place	Boston
Access Restriction	One Nation One Subscription (ONOS)
Subject Keyword	Pharmacy Pharmacology/Toxicology Biomedical Engineering Medical Law Biochemistry
Content Type	Text
Resource Type	Article
Subject	Organic Chemistry Pharmacology Molecular Medicine Pharmacology (medical) Biotechnology Pharmaceutical Science

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