Metabolic resistance mechanisms

As information on the molecular architecture and mechanisms of pesticide sites of action becomes more generally available and the nature and effect of mutations on their sensitivity to pesticides is defined, it should become possible in some cases to design agents that specifically interfere with the altered site of the resistant forms. The same line of reasoning suggests that the design of specific and selective synergists to block individual metabolic resistance mechanisms may eventually be possible. 

Metabolic resistance mechanisms are still the most widely encountered causes for OP and carbamate resistance. Yet, after the first few cases of target site insensitivity were reported in the early 1970 s in mites and ticks, many such cases have been found also in insects. Resistance can also be enhanced by a decreased rate of penetration through the integument. This resistance mechanism by itself is of minor importance, but provides an increased opportunity for detoxification. A 50-fold increase in resistance to carbaryl was seen in a house fly strain, in which a gene for reduced penetration had been combined (by selective breeding) with a gene for increased detoxification (5). 

To date, detection and management of resistance has predominantly been carried out with bioassays. These are essentially based on comparative growth of seedlings or plants of suspected resistant and sensitive weed biotypes subjected to different herbicide treatments [51-53]. Such bioassays are simple, but do not differentiate between target site and metabolic resistance mechanisms. 

It is fully recognized that resistance of insects and mites to insecticides and acaricides can, and frequently does, result from enhanced metabolism by enzymes overexpressed due to insecticide selection pressure. Such metabolic resistance mechanisms are not linked to any specific site of action classification and therefore they may confer cross-resistance to insecticides in more than one IRAC MoA group. Where such metabolic resistance has been characterized and the crossresistance spectrum is known, it is possible that certain alternations, sequences or rotations of MoA groups cannot be used. Similarly, mechanisms of reduced penetration of the pesticide into the pest, or behavioral changes of the pest, may also confer resistance to multiple MoA groups. Where such mechanisms are known to give cross-resistance between MoA groups, the use of insecticides should be modified appropriately. 

CYP6D1 of the housefly (Musca domestica) has been found to hydroxylate cyper-methrin and thereby provide a resistance mechanism to this compound and other pyrethroids in this species (Scott et al. 1998 see also Chapter 12). Also, this insect P450 can metabolize plant toxins such as the linear furanocoumarins xanthotoxin and bergapten (Ma et al. 1994). This metabolic capability has been found in the lepi-dopteran Papilio polyxenes (black swallowtail), a species that feeds almost exclusively on plants containing furanocoumarins. 

Resistance mechanisms associated with changes in toxicokinetics are predominately cases of enhanced metabolic detoxication. With readily biodegradable insecticides such as pyrethroids and carbamates, enhanced detoxication by P450-based monooxygenase is a common resistance mechanism (see Table 4.3). 

Resistance to DDT has been developed in many insect species. Although there are some cases of metabolic resistance (e.g., strains high in DDT dehydrochlorinase activity), particular interest has been focused on kdr and super kdr mechanisms based upon aberrant forms of the sodium channel—the principal target for DDT. There are many examples of insects developing resistance to dieldrin. The best-known mechanism is the production of mutant forms of the target site (GABA receptor), which are insensitive to the insecticide. 

Folate inhibitors, bacterial resistance mechanisms, 3 32t Folate metabolism, 23 502 Folcysteine, 13 431, 52 Folded guide microwave applicator, 16 522 Folding-carton inks, 14 321 Folding carton packaging, converting, 25 21-22... 

Our studies indicate that rapid metabolic detoxification of linear furanocoumarins is an effective resistance mechanism for K polyxenes against the toxic effects of these compounds. It has been postulated that the adaptation of some plants to produce angular furanocoumarins was in response to the reduced effectiveness of the linear furanocoumarins as deterrents for herbivores such as polyxenes (22). Such may Indeed be true, but our studies on the comparative detoxification of linear and angular furanocoumarins suggest that, at best, the presence of angular furanocoumarins in plants confers only a tenuous margin of relative "safety" against polyxenes. 

One obvious way to treat pathogens that have accumulated multiple resistance mechanisms or are intrinsically resistant to a given therapy is to use a drug with an entirely different mode of action. Since the major antifungal therapies target sterol biosynthesis or composition, a large variety of additional metabolic pathways are theoretically available. In reality,... 

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