Chemistry Reference
In-Depth Information
mechanism (Devonshire and Sawicki 1979; Devonshire 1991). AChE, the site of
action of OPs, is a B-esterase, which is highly sensitive to inhibition by oxons.
In addition to ester bonds with P (Section 10.2.1, Figures 10.1 and 10.2), some OPs
have other ester bonds not involving P, which are readily broken by esteratic hydroly-
sis to bring about a loss of toxicity. Examples include the two carboxylester bonds of
malathion, and the amido bond of dimethoate (Figure 10.2). The two carboxylester
bonds of malathion can be cleaved by B-esterase attack, a conversion that provides
the basis for the marked selectivity of this compound. Most insects lack an effec-
tive carboxylesterase, and for them malathion is highly toxic. Mammals and certain
resistant insects, however, possess forms of carboxylesterase that rapidly hydrolyze
these bonds, and are accordingly insensitive to malathion toxicity.
OP compounds are also susceptible to glutathione-S-transferase attack. Both R
groups and X groups can be removed by transferring them to reduced glutathione
to form a glutathione conjugate. As with oxidative dealkylation, an ionizable P-OH
group remains after removal of the substituted group, and the result is detoxication.
Diazinon, for example, can be detoxified by glutathione-dependent desethylase in
mammals and resistant insects.
Looking at the overall pattern of OP metabolism, it can be seen that there is often
competition between activating and detoxifying metabolic processes. Moreover,
many of these processes occur relatively rapidly. There are often marked differences
in the balance of these processes between species and strains, differences that may
be reflected in marked selectivity. As mentioned earlier, malathion is highly selective
between insects and mammals because most insects lack a carboxylesterase that can
detoxify the molecule. Some strains of insects (e.g., of
Tr iboliu m
castaneum
) owe
their resistance to the presence of such an esterase. Inhibition of B-esterase activity
with another OP (e.g., EPN) can remove this resistance mechanism and make the
resistant strain susceptible to malathion. Likewise, malathion becomes highly toxic
to mammals if administered together with a B-esterase inhibitor. The inhibitor acts
as a synergist. When rapid detoxication by carboxylesterase is blocked, consider-
able quantities of malathion are activated by monooxygenase to form malaoxon, and
toxicity is enhanced.
Diazinon, and the related insecticides pirimiphos-methyl and pirimiphos-ethyl,
are selectively toxic between birds and mammals (Environmental Health Criteria
198). All possess leaving groups derived from pyrimidine, and their oxon forms
are excellent substrates for mammalian A-esterases. Selectivity is largely explained
by the absence of significant A-esterase activity from the plasma of birds, an activ-
ity well represented in mammals (Machin et al. 1975; Brealey 1980; Brealey et al.
1980; Walker 1991; Machin et al. 1975). A-esterase activity is also low in avian liver
relative to that in mammalian liver. Diazinon is activated to diazoxon in the liver,
and toxicity then depends on the efficiency with which the latter can be transported
by the blood to its site of action (primarily AChE in the brain). In mammals, rapid
detoxication of oxons in the liver and blood gives effective protection against low
doses of these OPs. Birds are not so well protected; many species lack detectable
plasma A-esterase activity against oxon substrates (Mackness et al. 1987) and, on
available evidence, activity in liver is relatively low (Brealey 1980; Walker 1991).
Other OPs whose oxons are not good substrates for A-esterase (e.g., parathion) do
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