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pesticides, and often display a broad range of substrate specificity (
Bogaards et al., 1995;
Nebert et al., 1989
).
The numerous polymorphisms found in these CYP genes are of considerable
importance in the metabolism of xenobiotics, including pesticides. A polymorphism is
defined as an inherited monogenetic trait that exists in at least two genotypes (two or
more stable alleles) and is stably inherited. They arise as mutational events; if the muta-
tion is in the coding region a variant protein is expressed, thereby affecting the rate
and/or extent of metabolism and, potentially, the ratio of different metabolites and the
ratio of activation to detoxication.
The details of the interactions of CYPs with xenobiotics have been the subject of
intense study for some time, although in these studies clinical drugs have been uti-
lized to a much greater extent than pesticides. Despite the wide range of amino acid
sequence homology among CYP isoforms, all these isoforms have a remarkably simi-
lar reaction mechanism (
Figure 4.2
). CYP mono-oxygenation reactions all involve the
reduction of one atom of molecular oxygen to water and the incorporation of the
other oxygen atom into the substrate. The electrons involved in the reduction of CYP
are transferred from NADPH by the NADPH-cytochrome P450 oxidoreductase while,
in some cases, the second electron may be derived from NADH via cytochrome
b
5
.
Reviews of pesticide studies include
Hodgson and Kulkarni (1974)
,
Hodgson
(1974)
, and
Kulkarni and Hodgson (1980, 1984a,b)
. Studies of spectral interactions of
ROH
RH
Fe
3+
9
Fe
3+
ROH
Fe
3+
RH
1
8
NADPH-P450
reductase
1 e
-
FeOH
3+
R•
10
2
R'O
R'OOH
RH
Fe
2+
RH
7
FeO
3+
RH
O
2
H
2
O
3
6
Fe
2+
-O
2
RH
Fe
II
-OOH RH
4
5
1 e
-
NADPH-P450
reductase or NADH-
Cytochrome
b
5
reductase
Fe
2+
-O
2
-
RH
H
+
Figure 4.2
Catalytic cycle for cytochrome P450-catalyzed monooxygenation reactions.
(From Zeldin
and Seubert, 2008; adapted from F.P. Guengerich, 2001,
Chem. Res. Toxicol.
14:611-650.)
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