DNA and Double-Stranded Oligonucleotides - Free-Radical-Induced DNA Damage and Its Repair - page 427

studied contain nitro groups (for reviews see Adams et al. 1974, 1979; Adams
1977; Wardman 1977, 1984; Wardman and Clarke 1985; Durand and Olive 1981).
Typical examples are the nitroamidazoles misonidazole and metronidazole ('Fl-
agyl') which is most commonly used in the clinic (Wardman et al. 2003).

Nitro compounds may add to carbon-centered radicals and thus also with the
majority of the DNA radicals (Chap. 6.3; only the very strongly reducing radi-
cals such as e aq − and CO 2 • − reduce the nitro sensitizers to (unstable) hydroxyl-
amines; McClelland et al. 1984). Originally, the nitro compounds and O 2 have
just been taken as 'oxidants' irrespective of their mode of action, especially as
the efficiency of the sensitizers correlates with their reduction potential (Ad-
ams and Cooke 1969; Tallentire et al. 1972; Simic and Powers 1974; Adams et
al. 1976a, 1981). This concept is expressed in relationship (88), where C is the
sensitizer concentration required to achieve a constant sensitizing response (e.g.
an enhancement ratio of 1.6) and E 7 the one-electron reduction potential of the
sensitizer at pH 7.

log C = b 0 + b 1 E 7

− (89)

The electron affinity relationship (Table 12.25) does not uniquely apply to radia-
tion sensitization but also, for example, to toxicity (Olive 1980), and a warning
was expressed against drawing a firm conclusion from this relationship as to the
cause of the effect (Wardman and Clarke 1985).
In fact, with a few exceptions, neither O 2 nor nitro compounds react with free
radicals by ET (as would be required for an electron affinity relationship in its
proper sense) but rather undergo addition reactions. The ensuing radicals show
different decay routes as is discussed in Chapter 6.3. When DNA is irradiated
in deoxygenated aqueous solution in the presence of 14 C-labeled mitronidazole,
some of the sensitizer remains attached to DNA (Willson et al. 1974). Misonida-
zole and practically all other nitroimidazoles have a lower reduction potential
than O 2 , and much higher concentrations have to administered to achieve the
same effect (Whillans and Hunt 1982).
Some of the sensitizing (and cytotoxic) effects of the nitro compounds can be
attributed to GSH depletion. Activated chlorine may be replaced by GS − [reaction
(89); Wardman 1982; Stratford et al. 1983)], but the reaction is much more gen-
eral. For example, the 2-nitroimidazoles react with GS − by NO 2 − release. These
reactions are slow, but are considerably speeded up by glutathione- S -transferase
(Wardman et al. 1973).