oxidants and antioxidants in biology - Oxygen Club of California

Cytoprotective and cytotoxic effects of in vivo
flavonoid metabolites
CATHERINE RICE-EVANS
Wolfson Centre for Age-Related Diseases, King’s College, London, UK
In delineating the cytoprotective effects of flavonoids against
oxidative stress, few studies have considered the influence of gastrointestinal
and hepatic metabolism and the consequences of the
ensuing chemical structural changes on their biological properties
and activities. Here we present the factors influencing the differential
effects of three major classes of flavonoids, the flavonols – represented
by quercetin, the flavanols – represented by epicatchin,
and the flavanones – represented by hesperetin, and their corresponding
in vivo conjugates and metabolites, in protecting human
fibroblasts from cell death induced by peroxide-induced oxidative
stress. Modifications to flavonoids from aglycone to in vivo forms
include increasing polarity and lack of intracellular access through
glucuronidation, on the one hand, and decreasing polarity and as
well as modulation of redox properties through methylation of
catechol moieties, on the other hand.
The results show that epicatechin protects against apoptosis
induced by oxidative stress through mechanisms involving the
modulation of JNK-activation. Interestingly, its methylated forms
(with substituted catechol structures) are equally efficacious suggesting
the lack of requirement for the redox-active catechol moiety
in its mechanism of action. The glucuronide, however, is ineffective,
suggesting a requirement for intracellular access or that the
A-ring, modified on glucuronidation, might mediate specific binding.
In contrast, hesperetin (as well as its glucuronides) are neither
cytoprotective nor cyotoxic at the concentrations studied. In fact,
hesperetin is handled rather differently in that intracelluar metabolism
leads to glucuronidation and subsequent export from the cells.
The cellular interactions of quercetin (the most redox-active of
flavonoid structures) and its methylated metabolites yet again contrast
with those of the flavanol and flavanone and are dependent on
the precise structural chemistry of the metabolites and their abilities
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