Structural aspects of flavonoids as inhibitors of human butyrylcholinesterase

被引:162
作者
Katalinic, Maja [1 ]
Rusak, Gordana [2 ]
Barovic, Jelena Domacinovic [1 ,2 ]
Sinko, Goran [1 ]
Jelic, Dubravko [3 ]
Antolovic, Roberto [4 ]
Kovarik, Zrinka [1 ]
机构
[1] Inst Med Res & Occupat Hlth, HR-10000 Zagreb, Croatia
[2] Univ Zagreb, Fac Sci, Dept Biol, HR-10000 Zagreb, Croatia
[3] GlaxoSmithKline Res Ctr Zagreb, HR-10000 Zagreb, Croatia
[4] Univ Rijeka, Dept Biotechnol, HR-51000 Rijeka, Croatia
关键词
Acetylcholinesterase; Cholinesterase; Cytotoxicity; Flavonoids; UV-VIS spectra; Reversible inhibition; ALZHEIMERS-DISEASE; QUERCETIN; METABOLISM; TOXICITY; PATHWAYS; PRODUCTS; BRAIN; CELLS;
D O I
10.1016/j.ejmech.2009.09.041
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
Selected flavonoids: galangin, kaempferol, quercetin, myricetin, fisetin, apigenin, luteolin and rutin, reversibly inhibited human butyrylcholinesterase (BChE, EC 3.1.1.8). Inhibition potency of the flavonoids we attributed to their chemical structure, i.e., the number of OH groups and their side on the phenyl ring. The most potent BChE inhibitor among the tested flavonoids was galangin, which showed 12 times higher preference for binding to BChE (7 mu mol/L) than to the related enzyme human acetylcholinesterase (AChE, EC 3.1.1.7). Docking study showed that flavonoids bind to the BChE active site by forming multiple hydrogen bonds and pi-pi interactions. The UV-VIS (200-500 nm) absorption spectra of the flavonoid phosphate buffer solution (pH 7.4), with the exception of rutin, revealed time dependant changes indicating precipitation of flavonoids or in the case of myricetin, a change in the chemical structure resulting in a BChE non-inhibiting specie. Selected flavonoids showed no cytotoxic effect on HepG2 and A549 cell lines at concentrations up to 200 mu mol/L. Cytotoxicity was observed only for fisetin, apigenin and luteolin in the THP-1 cell line with IC50 of 30, 60 and 70 mu mol/L, respectively. (C) 2009 Elsevier Masson SAS. All rights reserved.
引用
收藏
页码:186 / 192
页数:7
相关论文
共 25 条
[1]   Fate of the flavonoid quercetin in human cell lines: Chemical instability and metabolism [J].
Boulton, DW ;
Walle, UK ;
Walle, T .
JOURNAL OF PHARMACY AND PHARMACOLOGY, 1999, 51 (03) :353-359
[2]  
Calic M, 2005, CROAT CHEM ACTA, V78, P367
[3]   Molecular mechanisms of anticancer activity of natural dietetic products [J].
Colic, M ;
Pavelic, K .
JOURNAL OF MOLECULAR MEDICINE-JMM, 2000, 78 (06) :333-336
[4]   Neurobiology of butyrylcholinesterase [J].
Darvesh, S ;
Hopkins, DA ;
Geula, C .
NATURE REVIEWS NEUROSCIENCE, 2003, 4 (02) :131-138
[5]   A NEW AND RAPID COLORIMETRIC DETERMINATION OF ACETYLCHOLINESTERASE ACTIVITY [J].
ELLMAN, GL ;
COURTNEY, KD ;
ANDRES, V ;
FEATHERSTONE, RM .
BIOCHEMICAL PHARMACOLOGY, 1961, 7 (02) :88-&
[6]   Butyrylcholinesterase, cholinergic neurotransmission and the pathology of Alzheimer's disease [J].
Geula, C ;
Darvesh, S .
DRUGS OF TODAY, 2004, 40 (08) :711-721
[7]  
Greig N.H., 2003, Butyrylcholinesterase: Its Function and Inhibitors, P69
[8]  
Gutzeit HO, 2005, CROAT CHEM ACTA, V78, P337
[9]   A critical review of the data related to the safety of quercetin and lack of evidence of in vivo toxicity, including lack of genotoxic/carcino genic properties [J].
Harwood, M. ;
Danielewska-Nikiel, B. ;
Borzelleca, J. F. ;
Flamm, G. W. ;
Williams, G. M. ;
Lines, T. C. .
FOOD AND CHEMICAL TOXICOLOGY, 2007, 45 (11) :2179-2205
[10]   Relative bioavailability of the antioxidant flavonoid quercetin from various foods in man [J].
Hollman, PCH ;
vanTrijp, JMP ;
Buysman, MNCP ;
VanderGaag, MS ;
Mengelers, MJB ;
deVries, JHM ;
Katan, MB .
FEBS LETTERS, 1997, 418 (1-2) :152-156