Biology Reference
In-Depth Information
the monooxygenase system, including aldrin, ethylmorphine, aniline, aminopyrene,
carbaryl, biphenyl, hexobarbital, and p -nitroanisole.
The inhibition, by organophosphorus compounds such as ethyl p -nitrophenol
thiobenzene phosphonate (EPN), of the carboxylesterase that hydrolyzes malathion
is a further example of xenobiotic interaction resulting from irreversible inhibition,
because in this case the enzyme is phosphorylated by the inhibitor. Oxons, such as
chlorpyrifos oxon, are potent inhibitors of the esterases, in humans, that hydrolyze
pyrethroids such as permethrin ( Choi et al., 2004 ).
Oxidative desulfuration of phosphorothioate pesticides such as chlorpyrifos, para-
thion, and fenitrothion by CYPs is known to release atomic sulfur, which covalently
binds to and inactivates CYPs ( Halpert et al., 1980; Kamataki and Neal, 1976; Levi
et al., 1988; Neal and Halpert, 1982 ). Administration of fenitrothion at a dose as low as
7 mg/kg inhibited the hydroxylation of 17β-estradiol by hepatic microsomes ( Berger
and Sultatos, 1996 ). Usmani et al. (2003, 2006) have shown that chlorpyrifos and
other OPs containing the P S moiety are potent inhibitors of the human metabo-
lism of both testosterone and estradiol. These results suggest that, in low concentrations,
organophosphorus insecticides have the potential to inhibit enzymes important in nor-
mal sexual development.
Another class of irreversible inhibitors of toxicological significance consists of those
compounds that bring about the destruction of the xenobiotic-metabolizing enzymes.
The drug allylisopropylacetamide, as well as other allyl compounds, has long been
known to cause the breakdown of CYPs and the resultant release of heme; the hepa-
tocarcinogen vinyl chloride has also been shown to have a similar effect, probably also
mediated through the generation of a highly reactive intermediate.
Synergism and Potentiation
The terms synergism and potentiation have been variously used and defined but, in
any case, involve a toxicity that is greater when two compounds are given simultane-
ously (or sequentially within a short time frame) than would be expected from a con-
sideration of the toxicities of the compounds given alone.
An example of synergism has already been mentioned. Piperonyl butoxide, sesa-
mex, and related compounds increase the toxicity of insecticides to insects by inhib-
iting insect CYPs. Other insecticide synergists that interact with CYP include
aryloxyalkylamines such as SKF-525A, Lilly 18947, and their derivatives; compounds
containing acetylenic bonds such as aryl-2-propynyl phosphate esters containing pro-
pynyl functions; phosphorothionates; benzothiadiazoles; and some imidazole deriva-
tives. Insecticide synergists have similar interactions with mammalian CYPs.
The best known example of potentiation involving insecticides and an enzyme
other than the monooxygenase system is the increase in the toxicity of malathion to
mammals that is brought about by certain other organophosphates. Malathion has a
low mammalian toxicity, due primarily to its rapid hydrolysis by a carboxylesterase.
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