Pyrethroid insecticides, metabolism

The organophosphorons insecticides dimethoate and diazinon are mnch more toxic to insects (e.g., housefly) than they are to the rat or other mammals. A major factor responsible for this is rapid detoxication of the active oxon forms of these insecticides by A-esterases of mammals. Insects in general appear to have no A-esterase activity or, at best, low A-esterase activity (some earlier stndies confnsed A-esterase activity with B-esterase activity) (Walker 1994b). Diazinon also shows marked selectivity between birds and mammals, which has been explained on the gronnds of rapid detoxication by A-esterase in mammals, an activity that is absent from the blood of most species of birds (see Section 23.23). The related OP insecticides pirimiphos methyl and pirimiphos ethyl show similar selectivity between birds and mammals. Pyrethroid insecticides are highly selective between insects and mammals, and this has been attributed to faster metabolic detoxication by mammals and greater sensitivity of target (Na+ channel) in insects. 

Tyler, C.R., Beresford, N., and van der Woning, M. et al. (2000). Metabolism and environmental degradation of pyrethroid insecticides produce compounds with endocrine activities. Environmental Toxicology and Chemistry 19, 801-809. 

Pyrethroid insecticides are rapidly metabolized to their inactive acids and alcohol components, which are excreted primarily in urine. A small portion of the absorbed compounds is excreted unchanged. Occupational exposure to pyrethroid insecticides can be assessed by measuring intact compounds or their metabolites in urine. Biological indicators of internal dose in exposed subjects are reported in Table 7. Due to their rapid metabolism, determination of blood concentrations can only be used to reveal recent high-level exposures. 

Flodstrom, S., L. Wamgard, S. Ljungquist, and U.G. Ahlborg. 1988. Inhibition of metabolic cooperation in vitro and enhancement of enzyme altered foci incidence in rat liver by the pyrethroid insecticide fenvalerate. Arch. Toxicol. 61 218-223. 

Riviere, J.L., J. Bach, and G. Grolleau. 1983. Effect of pyrethroid insecticides and N-(3,5-dichlorophenyl) dicarboximide fungicides on microsomal drug-metabolizing enzymes in the Japanese quail (Cotumix cotumix). Bull. Environ. Contam. Toxicol. 31 479-485. 

Pyrethroids have low oral toxicity to mammals, and in general their insect (topical) to mammal (oral) toxicity ratio is much higher than that of the other major classes of insecticides [25]. As the reason, at least the following mechanisms are conceivable (1) negative temperature dependence - differences in body temperature between insects and mammals makes the insect nerves much more sensitive, (2) metabolic rate - insects metabolize the insecticide more slowly than mammals, and the metabolizing enzyme systems are different, and (3) differences in body size - insects will have less chance to metabolize the insecticides before reaching the target site [26]. 

Crawford MJ, Croucher A, Hutson DH (1981) The metabolism of the pyrethroid insecticide cypermethrin in rats excreted metabolites. Pestic Sci 12 399—411... 

Casida JE, Ruzo LO (1980) Metabolic chemistry of pyrethroid insecticides. Pestic Sci 11 257-269... 

Godin SJ, Crow JA, Scollon EJ, Hughes MF, DeVito MJ, Ross MK (2007) Identification of rat and human cytochrome p450 isoforms and a rat serum esterase that metabolize the pyrethroid insecticides deltamethrin and esfenvalerate. Drug Metab Dispos 35 1664-1671... 

Nakamura Y, Sugihara K, Sone T, Isobe M, Ohta S, Kitamura S (2007) The in vitro metabolism of a pyrethroid insecticide, permethrin, and its hydrolysis products in rats. Toxicology 235 176-184... 

Kodaka R, Suzuki Y, Sugano T, Katagi T (2007) Aerobic metabolism and adsorption of pyrethroid insecticide metofluthrin in soil. J Pestic Sci 32 393-401... 

Leahey JP (1985) Metabolism and environmental degradation. In Leahey JP (ed) The pyrethroid insecticides, Chap 5. Taylor Francis, London, pp 263-342... 

Turning to tetrahydrophthalimide derivatives, we find the pyrethroid insecticide tetramethrin (4.191). In the rat, a major metabolic pathway involves... 

Temperature is one of the most important variables that determines the distribution and abundance of species (Cossins and Bowler 1987) and imposes critical limits on fitness. As a result of increasing metabolic rate, increasing temperature can increase the uptake and toxicity of contaminants by poikilothermic species, but may also increase rates of detoxification and excretion of toxicants (e.g., pyrethroid insecticides National Research Council of Canada [NRCC] 1987). Temperature extremes in themselves are stressful to organisms, causing induction of various stress proteins, which may be associated with fitness costs (Hoffmann et al. 2003). 

Natural and synthetic pyrethroid insecticides have been reviewed,100 and the synthesis of pyrethrins related to bioresmethrin has appeared (cf. Vol. 5, p. 16) 101 the fluorinated pyrethroid fluorethrin has been synthesized and is superior to bromethrin and resmethrin as an insecticide 102 the metabolism of cis- and trans-resmethrin in rats has been reported.103 Further papers report the synthesis104 and... 

The pyrethroid insecticide fenvalerate, (a-cyano-3-phenoxybenzyl-2-(4-chlorophenyl)isovalerate, contains two centers of chirality in its structure (designated as the 2 and a positions Fig. 19) and therefore four stereoisomers, two pairs of enantiomers are possible. Initial evaluation of the mixture, by addition to the diet of a number of species, resulted in granulomatous changes in the liver, lymph nodes, and spleen. Separation and evaluation of the individual stereoisomers indicated that the toxidty was associated with one of the four, the 2i ,a5-stereoisomer, and subsequent metabolic studies found the cause to be associated with the formation and disposition of a cholesterol ester of (i )-2-(4-chlorophenyl)isovalerate (Fig. 19). A metabolic transformation shown to be stereospedfic in mice, only the 2i ,a5-stereoisomer yielding the ester both in vitro and in vivo [159]. 

In this review, we have concentrated on the development of (1) in vivo metabolic data (i.e., and K, etc.), (2) QSAR, and (3) mechanistic models and their application for building PBPK/PD models. The development of the pyrethroid insecticides for agricultural and home use is complicated by their chemistry, in that they each possess one to four chiral centers, increasing the number of isomeric forms by a factor of 2 (where = the number of chiral centers). Isomer mixtures and individual isomers are commonly both subjected to testing for insecticidal activity. The fewer the number of active forms, the easier it is to test them for insecticidal activity, toxicity, and to buUd PBPK/PD models for them. The pyrethroids on which we focus in this review are presented in Table 2, along with their trivial and CAS names and their structures. Table Al (Appendix A) defines the acronyms and abbreviations used in the text, while Table A2 (Appendix A) defines the chemical and mathematical expressions that are presented in this review. 

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