The antioxidant vitamins C and E

in vitro experiments have shown that α-tocopherol in low-density lipoprotein (LDL)
can act as a prooxidant in the absence of vitamin C (17–19), and evidence for a prooxidant
effect of α-tocopherol in vivois mounting (19).
There are several properties that make ascorbate such a strong physiologic
antioxidant, including the low one-electron reduction (or redox) potentials of ascorbate
(282 mV) and its one-electron oxidation product, the ascorbyl radical (−174 mV)
(15). These low reduction potentials enable ascorbate and its radical to spontaneously
react with and reduce most physiologically relevant radicals and oxidants, i.e., these
reactions are energetically or thermodynamically feasible (Table 3.1). Indeed, it has
been stated that vitamin C acts “as the terminal water-soluble small molecule antioxidant”
in biological systems (15). Second, the second-order rate constants for the reactions
of ascorbate and most physiologically relevant ROS and RNS are greater than
10 5 (mol/L) −1 ·s −1 (Table 3.1), which makes these reactions highly competitive with
those of the same ROS and RNS with biological macromolecules. Third, the ascorbyl
radical formed from ascorbate upon one-electron oxidation is quite stable and unreactive,
due to resonance stabilization of the unpaired electron (15). Importantly, the
ascorbyl radical does not react with molecular oxygen (O 2 ) to form a more reactive
peroxyl radical. Instead, the ascorbyl radical readily dismutates to ascorbate and dehydroascorbic
acid (DHA). DHA is reduced back to ascorbate in biological systems,
e.g., by glutathione, glutaredoxin, or thioredoxin reductase, or is rapidly and irreversibly
hydrolyzed (1,20) (Scheme 3.1). Thus, a fourth reason that ascorbate is an
effective physiologic antioxidant is that it can be regenerated from its oxidized forms,
either by spontaneous chemical reactions or enzymatically.
Iron
Iron is the most abundant transition metal in biological systems. The total amount of
iron in a normal adult human has been estimated to be ~4.5 g (21), most of it in hemoglobin.
Iron is also one of the most abundant elements in the earth’s crust; however,
the large amount of iron in all living cells cannot be explained by this fact alone. The
preference of iron as a biologically relevant metal is related to its unique physicochemical
properties, allowing it to vary its oxidation state, redox potential, and elec-
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Scheme 3.1