Flavonoid, as a potent antioxidant, exerts many beneficial effects
in type 2 diabetes, whereas the prooxidative property may be also
important in vivo if copper is involved. Here, we chose an insulin
receptor kinase domain fragment (KK-1, residues 1126–1165),
containing the A-loop of the receptor as well as three key autophosphorylation
sites (Tyr1158, Tyr1162, and Tyr1163) associated with receptor signal transduction to investigate the
roles and the structure–activity relationship of three antidiabetic
flavonoids (kaempferol, luteolin, and apigenin) and two others with
a similar structure (diosmetin and genistein), on modulation of Cu(II)-mediated
tyrosine nitration and the corresponding effect on its functional
phosphorylation in the Cu2+/H2O2/NO2
– system. We found that both properties
of flavonoid played roles on inhibition of Cu(II)-mediated protein
nitration in the H2O2/NO2
– system: (1) on the one hand, flavonoid scavenged free radicals as
antioxidants, inhibited tyrosine nitration, and thus inhibited the
reduction of tyrosine phosphorylation caused by tyrosine nitration;
and (2) on the other hand, flavonoid promoted •OH
production as a prooxidant, which increased 3,3′-dityrosine
formation. The formation of 3,3′-dityrosine decreased Cu2+-induced tyrosine nitration and thus interfered with its
phosphorylation. This study confirms that the weight relationship
between antioxidation and prooxidation of a flavonoid needs to be
studied clearly before nutritional and medical applications.