Mechanisms Of Resistance And Their Homology

Depending on the mechanism involved, resistance has been shown to arise through structural alterations of genes encoding target-site proteins or detoxifying enzymes, or through processes affecting gene expression (e.g., amplification or altered transcription). Examples of the former include the following.

• Enhanced metabolism of insecticides by cytochrome ?450 monoxygenases can potentially confer resistance to most chemical classes. Much of the evidence for this mechanism is indirect, based on the ability of monoxygenase inhibitors to reduce the magnitude of resistance when used in combination with insecticides in bioassays.

• Enhanced activity of glutathione ¿"-transferases (GSTs) is considered to be potentially important in resistance to some classes of insecticide, including organophosphates. Like monoxygenases, GSTs, exist in numerous molecular forms with distinct properties, making correlations of enzyme activity with resistance very challenging and often ambiguous.

• Enhanced hydrolysis or sequestration by esterases (e.g., carboxylesterases) capable of binding to and cleaving carboxylester and phosphotriester bonds undoubtedly plays an important role in resistance to organophosphates and pyrethroids. Biochemically, this is the best-characterized detoxification mechanism. Sometimes (e.g., for mosquitoes, blowflies, and M. persicae) the esterases have been identified and sequenced at the molecular level. Resistance caused by increased esterase activity can arise through a qualitative change in an enzyme, improving its hydrolytic capacity, or (as in mosquitoes and aphids) a quantitative change in the titer of a particular enzyme that already exists in susceptible insects.

The following examples appear to show that although some adaptations to the environment are unpredictable (e.g., the modifications of the forelimbs for flight are very different in birds, bats, and pterodactyls), the opportunities for insects to modify or reduce binding of insecticides, hence to develop target-site-based resistance mechanisms, are very limited indeed. It is conceivable that most of the mutations that confer such resistance do not allow the organism to retain normal functioning of the nervous system.

• Pyrethroids act primarily by binding to and blocking the voltage-gated sodium channel of nerve membranes. Knockdown resistance, or insensitivity of this target site, is now unequivocally attributed to structural modifications in a sodium channel protein. The same amino acid substitution (leucine 1014 to phenylalanine) in a sodium channel protein confers a "basal" kdr phenotype in a range of species including house flies, cockroaches, the green peach aphid, the diamondback moth, and a mosquito (A. gambiae). This phenotype may subsequently be enhanced (to "super-kdr" resistance) by further mutations that also recur between species.

• GABA receptors are targets for several insecticide classes including cyclodienes (a subclass of the organochlorines), avermectins, and fipronils. The primary mechanism of resistance to cyclodienes and fipronils involves modification of a particular GABA receptor subunit, resulting in substantial target-site insensitivity to these insecticides. The target-site mechanism of cyclodiene resistance has been attributed to the same amino acid substitution (alanine 302 to serine) in the GABA receptors of several species of diverse taxonomic origin including Drosophila, several beetles, a mosquito (Aedes aegypti), a whitefly (B. tabaci), and a cockroach (Blatella germanica). When susceptible individuals of the sheep blowfly (L. cuprina) were exposed to the mutagen ethyl methanesulfonate (EMS), and their progeny screened for resistance to dieldrin (a cyclodiene), surviving insects exhibited an alanine-to-serine amino acid substitution in the GABA receptor identical to that found in nature.

• Organophosphates and carbamates exert their toxicity by inhibiting the enzyme acetylcholinesterase (AChE), thereby impairing the transmission of nerve impulses across cholin-ergic synapses. Mutant forms of AChE showing reduced inhibition by these insecticides have been demonstrated in several insect and mite species. Biochemical and molecular analyses of insecticide-insensitive AChE have shown that pests may possess several different mutant forms of this enzyme with contrasting insensitivity profiles, thereby conferring distinct patterns of resistance to these two insecticide classes.

Some of these resistance mechanisms are illustrated schematically in Fig. 2.

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