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O
2
•-
O
2
3-Nitropyrene
R-NO
2
-
R-NO
2
R =
e
O
2
•-
O
2
•
+
+
CH
3
+
NCH
3
NCH
3
Free radical
Paraquat
CH
3
N
e
fIgure 13.2
Superoxide generation by 3-nitropyrene and paraquat.
At the time of writing, the toxicity of oxyradicals generated by the action of pol-
lutants is highly topical because of the relevance to human diseases. It is not an
easy subject to investigate because of the instability of the radicals and the different
mechanisms by which they may be generated. Hopefully rapid progress will be made
so that monitoring the effects of oxyradicals will make an important contribution
to the growing armory of mechanistic biomarkers for the study of environmental
effects of organic pollutants.
Viewing the foregoing examples overall, the first five all involve interaction
between organic pollutants and discrete sites on proteins, one of them the active
site of an enzyme, the others being “receptors” to which chemicals bind to produce
toxicological effects. Knowledge of the structures and properties of such receptors
facilitates the development of QSAR models for pollutants, where toxicity can be
predicted from chemical parameters (Box 17.1). Indeed, new pesticides are some-
times designed on the basis of models of this kind. For example, some ergosterol
synthesis inhibitor fungicides (EBIs) that can lock into the catalytic site of P450s
have been discovered by following this approach. Interactions such as these are
essentially similar to the interactions of agonists and/or antagonists with receptors
in pharmacology.
The last two examples do not belong in the same category, there being no discrete
single binding site on a protein. Uncouplers of oxidative phosphorylation operate
across the inner mitochondrial membranes, their critical properties being the ability
to reversibly interact with protons and their existence in the uncharged lipophilic
state after protons are bound. Oxyradicals can, in principle, be generated by a variety
of redox systems in differing locations, which are able to transfer single electrons to
oxygen under cellular conditions. The systems that carry out one electron reduction
of nitroaromatic compounds and aromatic amines have yet to be properly elucidated.
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