Chemistry Reference
In-Depth Information
10.2.2 m
e T a b o l i s m
As examples of OP metabolism, the major metabolic pathways of malathion, diazi-
non, and disyston are shown in Figure 10.2, identifying the enzyme systems involved.
OPs are highly susceptible to metabolic attack, and metabolism is relatively complex,
involving a variety of enzyme systems. The interplay between activating transfor-
mations on the one hand, and detoxifying transformations on the other, determines
toxicity in particular species and strains (see Walker 1991). Because of this complex-
ity, knowledge of the metabolism of most OPs is limited. Further information on OP
metabolism may be found in Eto (1974), Fest and Schmidt (1982), and Hutson and
Roberts (1999).
All three insecticides shown in Figure 10.2 are thions, and all are activated by
conversion to their respective oxons. Oxidation is carried out by the P450-based
microsomal monooxygenase system, which is well represented in most land verte-
brates and insects, but less well represented in plants, where activities are very low.
Oxidative desulfuration of thions to oxons does occur slowly in plants, and may be
due to monooxygenase attack and peroxidase attack (Drabek and Neumann 1985;
Riviere and Cabanne 1987). Compounds, such as disyston, which have thioether
bridges in their structure, can undergo sequential oxidation to sulfoxides and sulfones.
Other examples are demeton-
S
-methyl (Figure 10.1) and phorate. The oxon forms of
OP sulfoxides and sulfones can be potent anticholinesterases, and sometimes make
an important contribution to the systemic toxicity of insecticides, such as demeton-
S
-methyl, disyston, and phorate.
The oxidation of OPs can bring detoxication as well as activation. Oxidative attack
can lead to the removal of R groups (oxidative dealkylation), leaving behind P-OH,
which ionizes to PO
−
. Such a conversion looks superficially like a hydrolysis, and was
sometimes confused with it before the great diversity of P450-catalyzed biotransfor-
mations became known. Oxidative deethylation yields polar ionizable metabolites and
generally causes detoxication (Eto 1974; Batten and Hutson 1995). Oxidative demethy-
lation (O-demethylation) has been demonstrated during the metabolism of malathion.
The bond between P and the “leaving group” (X) of oxons is susceptible to esterase
attack, the cleavage of which represents a very important detoxication mechanism.
Examples include the hydrolysis of malaoxon and diazoxon (see Figure 10.2). Such
hydrolytic attack depends on the development of
d
+
on P as a consequence of the
electron-withdrawing effect of oxygen. By contrast, thions are less polarized and
are not substrates for most esterases. Two types of esterase interact with oxons (see
Chapter 2, Figure 2.9 and Section 2.3.2.3). A-esterases continuously hydrolyze them,
yielding a substituted phosphoric acid and a base derived from the leaving group as
metabolites. B-esterases, on the other hand, are inhibited by them, the oxons acting
as “suicide substrates.” With cleavage of the ester bond and release of the leaving
group, the enzyme becomes phosphorylated and is reactivated only very slowly. If
“aging” occurs it is not reactivated at all. Thus, continuing hydrolytic breakdown
of oxons by B-esterases is, at best, slow and inefficient. Nevertheless, B-esterases
produced in large quantities by resistant aphids can degrade or sequester OPs to a
sufficient extent to substantially lower their toxicity and thereby provide a resistance
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