Biology Reference
In-Depth Information
EPN, another organophosphorus insecticide, causes a dramatic increase in malathion
toxicity to mammals at dose levels that, given alone, cause essentially no inhibition of
cholinesterase. In vitro studies have shown that the oxygen analog of EPN, as well as
oxons of many other organophosphate compounds, increases the toxicity of malathion
by inhibiting the carboxylesterase responsible for its degradation.
Antagonism
In toxicology, antagonism may be defined as that situation in which the toxicity of
two or more compounds administered together (or sequentially within a short time
frame) is less than would be expected from a consideration of their toxicities when
administered individually. Apart from the effects mediated through induction of
XMEs (discussed previously), antagonism does not appear to be important in pesticide
interactions.
Pesticides as Inhibitors
Examples of pesticides as inhibitors of the metabolism of other pesticides, other xeno-
biotics, or endogenous metabolites in humans are shown in Table 7.3 . Pesticides may
act to inhibit CYPs or other enzymes by any of the mechanisms discussed previ-
ously—competitive inhibition, noncompetitive inhibition, or irreversible inhibition.
As discussed more fully in the following section, MDP compounds have very com-
plex interactions with the CYP system, being both inhibitors and inducers. Because
MDP compounds are substrates for CYP enzymes, they may act initially as competi-
tive inhibitors. As the MDP compound is metabolized, it becomes a suicide inhibitor
with its reactive metabolite bound to the heme iron of CYP ( Goldstein et al., 1973;
Hodgson et al., 1998; Hodgson and Philpot, 1974 ).
The herbicide synergist tridiphane, a postemergent herbicide, owes its activity to
its ability to inhibit glutathione S -transferases. It has also been shown to induce epox-
ide hydrolase and CYP, specifically CYP4A, and peroxisomal enzymes ( Levi et al., 1992;
Moody and Hammock, 1987 ). In addition to induction of CYP4A, tridiphane functions
as a selective CYP inhibitor, inhibiting CYP2B10 while having little or no effect on other
CYP isoforms ( Moreland et al., 1989 ). As assessed by in vitro studies, tridiphane appears to
be a competitive inhibitor of CYP; its effect in vivo, however, is not yet known.
Organophosphorus insecticides such as chlorpyrifos, parathion, and others that
contain the P S moiety are metabolized by the CYP system to the corresponding
oxon, P O, by oxidative desulfuration. This activation reaction, which converts the
relatively inactive compound to a potent cholinesterase inhibitor, is thought to involve
the formation of a P-S-O (phosphooxythirane) ring intermediate. Studies with both
microsomes and purified enzymes ( Halpert et al., 1980; Kamataki and Neal, 1976;
Morelli and Nakatsugawa, 1978 ) have demonstrated that, during oxidative desulfur-
ation, the released sulfur exists as a highly reactive molecule that then binds to the
heme iron of CYP, inactivating the enzyme. This binding of reactive sulfur to CYP is
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