Inhibition of the sarcoplasmic/endoplasmic reticulum Ca2+‐ATPase by flavonoids: A quantitative structure‐activity relationship study

Flavonoids are commonly found in fruit and vegetables and have been shown to reach concentrations of several micromolars in human blood plasma. Flavonoids are also believed to have cancer chemoprotective properties. One hypothesis is that flavonoids are able to initiate apoptosis, especially in canc...

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Published in:IUBMB life 2008-12, Vol.60 (12), p.853-858
Main Authors: Ogunbayo, Oluseye A., Harris, Robert M., Waring, Rosemary H., Kirk, Christopher J., Michelangeli, Francesco
Format: Article
Language:English
Subjects:
Animals
Brain - drug effects
Brain - enzymology
Ca2+‐ATPase
Calcium - metabolism
Calcium Signaling - drug effects
Cytoplasm - metabolism
Endoplasmic Reticulum - drug effects
Endoplasmic Reticulum - enzymology
Enzyme Inhibitors - pharmacology
flavonoid
Flavonoids - pharmacology
Microsomes - drug effects
Microsomes - enzymology
Mitochondria - drug effects
Mitochondria - metabolism
Muscle, Skeletal - enzymology
phytoestrogen
QSAR
Quantitative Structure-Activity Relationship
quercetin
Rabbits
Sarcoplasmic Reticulum - drug effects
Sarcoplasmic Reticulum - enzymology
Sarcoplasmic Reticulum Calcium-Transporting ATPases - antagonists & inhibitors
Sarcoplasmic Reticulum Calcium-Transporting ATPases - metabolism
SERCA
Swine
Thapsigargin - pharmacology
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Summary:Flavonoids are commonly found in fruit and vegetables and have been shown to reach concentrations of several micromolars in human blood plasma. Flavonoids are also believed to have cancer chemoprotective properties. One hypothesis is that flavonoids are able to initiate apoptosis, especially in cancer cells, via a Ca2+‐dependent mitochondrial pathway. This pathway can be activated through an exaggerated elevation of cytosolic [Ca2+], and sarcoplasmic/endoplasmic reticulum Ca2+‐ATPases (SERCA) play an essential role in ameliorating such changes. In this study, we demonstrate that flavonoids (especially flavones) can inhibit the activity of Ca2+‐ATPases isoforms SERCA1A and SERCA2B in the micromolar concentration range. Of the 25 flavonoids tested, 3,6‐dihydroxyflavone (IC50, 4.6 μM) and 3,3′,4′,5,7‐pentahydroxyflavone (quercetin) (IC50, 8.9 μM) were the most potent inhibitors. We show that polyhydroxylation of the flavones are important for inhibition, with hydroxylation at position 3 (for SERCA1A) and position 6 (for SERCA2B) being particularly relevant. © 2008 IUBMB IUBMB Life, 60(12): 853–858, 2008
ISSN:1521-6543
1521-6551
DOI:10.1002/iub.132