Biomedical subjects
Publications and source records attributed to R L Metcalf.
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Despite the immense utility of DDT for vector control its usefulness is prejudiced by its stability in the environment and by the low rate at which it can be degraded biologically. Metabolic studies in insects, in mice, and in a model ecosystem with several food chains have shown that DDT analogues with substituent groups readily attacked by multifunction oxidases undergo a substantial degree of biological degradation and do not appear to be stored readily in animal tissues or concentrated in food chains. Detailed metabolic pathways have been worked out and it is clear that comparative biochemistry can be used to develop DDT analogues that are adequately persistent yet biodegradable. A number of new DDT analogues have been evaluated for insecticidal activity against flies and mosquitos and for their potential usefulness as safe, persistent, and biodegradable insecticides.
Carbamate insecticides are biologically active because of their structural complementarity to the active site of acetylcholinesterase (AChE) and their consequent action as substrates with very low turnover numbers. Carbamates behave as synthetic neurohormones that produce their toxic action by interrupting the normal action of AChE so that acetylcholine accumulates at synaptic junctions. The necessary properties for a suitable insecticidal carbamate are lipid solubility, suitable structural complementarity to AChE, and sufficient stability to multifunction-oxidase detoxification. The relationships between the structure and the activity of a large number of synthetic carbamates are analysed in detail, with particular attention to the second of these properties.
Cholinesterase from frozen sections of honey bee (Apis mellifera, L.) brain hydrolyzes phenylthioacetate and acetylthiocholine to give virtually identical patterns of enzyme distribution with and without the use of paraoxon. In addition, phenylthioacetate is an economical substrate for in vitro and in vivo studies of cholinesterase. Phenylthioacetate offers the advantages of being easily synthesized and lipoid soluble, and appears to penetrate membranes easily.
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Toxicity tests on Culex pipiens fatigans with propoxur (o-isopropoxyphenyl methylcarbamate) and carbofuran (2,2-dimethyl-2,3-dihydrobenzofuranyl-7-methylcarbamate) indicated that both compounds are fast-acting insecticides. Transfer of treated larvae to fresh water results in their partial recovery from knockdown.Propoxur is metabolized by resistant and susceptible larvae by their homogenate-reduced nicotinamide-adenine dinucleotide phosphate (NADPH(2)) enzyme system and by the microsome-plus-soluble fraction of mouse-liver extracts to at least 10 organosoluble metabolites with the isopropoxy group intact. The major metabolites, which are primarily hydroxylation products or the result of degradation of these products, have tentatively been identified as: acetone plus o-hydroxyphenyl methylcarbamate, 2-isopropoxy-5-hydroxyphenyl methylcarbamate, 2-isopropoxyphenyl carbamate, and 2-isopropoxyphenyl N-hydroxymethylcarbamate. Upon incubation of water-soluble products from treated larvae with beta-glucosidase, beta-glucuronidase, aryl sulfatase and acid phosphatase, the conjugates are hydrolysed, liberating mainly hydroxylated carbamates.The results indicate that slower absorption as well as faster detoxification by hydroxylation mechanisms, together with conjugation with polar molecules and elimination, are major factors in resistance of mosquito larvae to substituted-aryl methylcarbamate insecticides.
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Studies of the comparative toxicity of more than 120 DDT analogues to susceptible and insecticide-resistant houseflies (Musca domestica L.) and mosquitos (Culex fatigans Wiedemann and Anopheles albimanus Wiedemann) have shown that the relative effectiveness of these compounds against DDT-resistant insects is correlated with the susceptibility of the molecule to attack by DDT-ase at the benzylic hydrogen. Compounds highly effective against DDT-resistant flies and mosquitos are produced by blocking this detoxication mechanism by o-chlorination, alpha-fluorination, and by altering the aliphatic portion of the molecule as in the nitropropyl, neopentyl, dichlorocyclopropyl, and trichlorobenzanilide derivatives. These compounds offer practical possibilities for the control of DDT-resistant insects. The correlation of structure, DDT-like activity, and resistance ratios gives new insight into the mode of action of DDT and the nature of DDT resistance.