Abstract
The plasma membrane oxidoreductase (PMOR) activity, which mainly utilises ascorbate as intracellular electron donor, represents a major mechanism for cell-dependent reduction of extracellular oxidants and might be an important process used by the erythrocytes to keep a reduced plasma environment. We previously reported that in human erythrocytes, myricetin and quercetin act as intracellular substrates of a PMOR showing a novel mechanism whereby these flavonoids could exert beneficial effects under oxidative stress conditions. Here, we evaluated the ability of different flavonoids (quercetin, myricetin, morin, kaempferol, fisetin, catechin, luteolin, apigenin, acacetin, rutin, taxifolin, naringenin, genistein) and of two in vivo O-methylated metabolites of quercetin (isorhamnetin and tamarixetin) to be substrates of PMOR, by comparing their antioxidant capacity (i.e. direct interaction with the oxidant ferricyanide or with the free radical 1,1-diphenyl-2-picryl-hydrazil) with their ability to penetrate the erythrocytes and donate electrons to the PMOR. The results obtained indicate that, although most of the flavonoids display significant antioxidant activities, only those (quercetin, myricetin, fisetin) that combine the cathecol structure of the B ring (responsible for the reducing activity) with the 2,3 double bond and 4-oxo function of the C ring (responsible for the uptake by erythrocytes) can act as intracellular substrates for PMOR. It is of note that the metabolites of quercetin enter erythrocytes and donate electrons to the PMOR as the parent compound. The present data show a relationship between the flavonoid structures and their ability to provide electrons to the PMOR, suggesting an additional mechanism whereby dietary flavonoids may exert beneficial effects in man.
Highlights
It is well established that diets rich in fruits and vegetables are protective against the oxidative effects of reactive oxygen species, which are formed in vivo during the cellular aerobic metabolism and can cause damage to various cellular components such as DNA, proteins, lipids, etc (Steinmetz & Potter, 1991a,b; Keli et al 1996; Ness & Powles, 1997; Ross & Kasum, 2002)
Many of the biological actions of flavonoids have been attributed to their antioxidant properties (Afanas’ev et al 1989; Bors et al 1990; Rice-Evans et al 1997); more recently, it has been proposed that flavonoids and their metabolites may exert their effects by displaying modulatory actions in cells (Williams et al 2004)
We have previously reported that flavonoids quercetin and myricetin are efficiently taken up by human erythrocytes and can act as substrates for the plasma membrane oxidoreductase (PMOR) activity, suggesting another mechanism whereby flavonoids can exert their protective effects (fax þ 0722 320188 (Fiorani) et al 2002)
Summary
It is well established that diets rich in fruits and vegetables are protective against the oxidative effects of reactive oxygen species, which are formed in vivo during the cellular aerobic metabolism and can cause damage to various cellular components such as DNA, proteins, lipids, etc (Steinmetz & Potter, 1991a,b; Keli et al 1996; Ness & Powles, 1997; Ross & Kasum, 2002). We have previously reported that flavonoids quercetin and myricetin are efficiently taken up by human erythrocytes and can act as substrates for the plasma membrane oxidoreductase (PMOR) activity, suggesting another mechanism whereby flavonoids can exert their protective effects (Fiorani et al 2002). This enzyme activity represents an important means to defend the cells against extracellular oxidative stressors (May et al 1996), and since the erythrocytes are constantly exposed to oxidative stress, it might have a major role in maintaining a reduced plasma environment (Kennett & Kuchel, 2003). The aim of the present study was to evaluate the ability of several flavonoids (Fig. 1), commonly present in fruits and vegetables (flavonols: quercetin, myricetin, morin, kaempferol, fisetin; flavanol: catechin; flavones: luteolin, apigenin, acacetin, rutin; flavanones: taxifolin and naringenin; isoflavone: genistein) and of two reported in vivo quercetin metabolites, isorhamnetin and tamarixetin (Spencer et al 2003a), to interact with human erythrocyte plasma membrane and induce extracellular reduction of oxidants
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