Metabolic resistance

Metabolic resistance may be the consequence of the appearance of a novel gene on the resistant strain, which is not present in the general population it may also be due to the presence of multiple copies of a gene in different strains or clones as in the example of OP resistance in the peach potato aphid mentioned earlier. 

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. 

P.Z. Tan, R.M. Baldwin, T. Fu, D.S. Charney, R.B. Innis, Rapid synthesis of F-18 and H-2 dual-labeled altanserin, a metabolically resistant PET ligand for 5-HT2A receptors, J. Label. Compds Radiopharm. 42 (1999) 457-467. 

Other azepane derivatives of interest include some protein kinase B inhibitors <2004JME1375>, and 3-(acylamino)-azepan-2-ones as metabolically-resistant broad spectrum chemokine inhibitors <2005JME867>. 

This characteristic, however, is not universally found in all triazine-resistant weeds. Gray et al. (1995a, b) found that velvetleaf resistance to atrazine in Wisconsin was not associated with a reduction in fitness, productivity, or intraspecific competitive ability. This triazine-resistant species found in Maryland and Wisconsin does not have D1 level resistance in the chloroplasts, but instead has a more rapid metabolic detoxification of triazines in these biotypes. The extent of the rapid metabolic resistance in other velvetleaf-resistant biotypes is unknown. 

Li, X., Schuler, M.A., and Berenbaum, M.R., Molecular mechanisms of metabolic resistance to synthetic and natural xenobiotics, Anna. Rev. Entomol, 52, 231, 2007. 

Our understanding of DOM composition and cycling has undergone a rapid change since the 1990s. Chemical studies of HMW DOM now show a composition that is rich in specific polysaccharides and proteins and remarkably uniform across diverse environments. These discoveries led Aluwihare et al. (1997) to propose that a major fraction of HMW DOM arises directly from biosynthesis. The concept that marine DOM has a large component of metabolically resistant bioploymers is a sharp departure from earlier ideas that described DOM as a mixture of simple biomolecules that had experienced abiotic transformation (geopolymerization) into HMW substances (fulvic and humic substances). Support for the directly formed biopolymer hypothesis comes from the chemical composition of HMW DOM itself. 

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. 

Organophosphates (OPs), introduced in 1944, and carbamates, introduced in 1956, remain widely used and effective insecticides although not free from resistance problems. Metabolic resistance to OPs was reported 14 years after their introduction, compared to only 7 years for DDT and 5 for the carbamates. The complex metabolic fate of the OPs, including attack by cytochrome P-450 leading either to activation or detoxification, as well as by glutathione transferases and esterases, may play a role in this delay. Carbamates are not bioactivated they are detoxified by cytochrome P-450. 

In the presence of a continued selection pressure, metabolic resistance may facilitate the evolution of other defenses such as target site resistance, reported for the OPs and carbamates 6 and 10 years after metabolic resistance. Target site resistance to OPs and carbamates resides in modified forms of acetyl-cholinesterases (AChEs) with reduced affinity for the insecticides. AChE-based target site resistance does not necessarily confer cross resistance to all other OPs and carbamates and may be unstable in the absence of a selection pressure. 

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). 

Evolution of metabolic resistance to the OPs. The following is an attempt to understand why it took such an unusually long time for insects to evolve metabolic resistance to the OPs Clearly, the selection pressure is diluted by having to act on three different, genetically unrelated enzyme systems, all of which detoxify the com-... 

Target site resistance to OPs was first reported in 1964, 20 years after their introduction, in a spider mite (53) and subsequently in several insect species including the green rice leaf hopper (54), mosquitoes (5 ), house flies (56-58, and an armyworm (59). Target site resistance to the carbamates was first observed in 1971 (60). It is, today, a common form of resistance to these insecticides and always combined with metabolic resistance. 

Target site resistance can be diagnosed in vivo by the use of synergists, which block detoxification but have no effect if the target site is insensitive or protected. When target site resistance is combined with metabolic resistance, the use of synergists can partially but not fully reverse the resistance. Alternatively, target site... 

Since the discovery of hydantoin in 1861, when Baeyer isolated it in his uric acid studies, that system has been an important precursor of a-amino acids owing to its lability toward alkali, especially for those acids that are difficult to prepare by other methods.300 Furthermore, the stereochemical courses of the Bucherer-Bergs and Read methods of synthesis for hydantoins (Section II,E), permit the preparation of epimeric amino acids.301-305 Some of these amino acids have been tested as possible tumor growth inhibitors,306,307 as metabolism-resistant amino acid analogues for transport system studies,72,308... 

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