Target-site sensitivity

We have, therefore, been able to indirectly assess the importance of three factors involved in chlorinated alicyclic insecticide resistance in mosquitofish disposition, metabolism and target site sensitivity. In a highly polluted environment in which mosquitofish have been placed under severe selective pressures by chronic exposure to insecticides, the system of metabolism appears to be of little significance in resistance the... 

Yu and Nguyen (1996) showed that selection of a strain of diamondback moth (Plu-tella xylostella) with permethrin for 21 generations resulted in over 600-fold resistance to permethrin in this strain. The resistant strain was also cross-resistant to all pyrethroids tested, including bifenthrin, fenvalerate, esfenvalerate, A.-cyhalothrin, fluvalinate, and tral-omethrin. However, it remained susceptible to organophosphate, carbamate, cyclodiene, neonicotinoid, avermectin, and microbial insecticides tested. Biochemical studies indicated that pyrethroid resistance observed in this strain was most likely due to decreased target site sensitivity. 

Pyrethroid insecticides (deltamethrin, NRDC 157, cismethrin), DDT analogs ( p,j> -DDT, (>,j> -DDT, methoxychlor, EDO), and a DDT-pyrethroid hybrid compound (GH401) enhanced veratridine-dependent sodium uptake by mouse brain synaptosomes The effectiveness of these compounds in the sodium uptake assay was in good agreement with their acute mammalian toxicities. , -DDT also enhanced veratridine-dependent sodium uptake by fish brain synaptosomes These findings demonstrate the utility of ion flux assays to study interactions of insecticides with sodium channels in the central nervous system and to explore species differences in insecticide target site sensitivity ... 

Two factors are most commonly associated with the development of pesticide resistance in arthropods enhanced metabolic detoxification and/or decreased target site sensitivity. Other factors that sometimes come into play are reduction in the rate at which a toxicant is absorbed into the body, or in the rate at which it is translocated to the site of action. In rare cases, there may be behavioral adaptations which allow the arthropod to minimize contact with the toxicant (25-22.) ... 

Table 4.1.1 presents IC50S of commercial herbicides for inhibition of carotenoid biosynthesis obtained in vivo according to Ref [26). The assay is easier to run than the early radioactive approach with unicellular cyanobacteria [35], giving in three cases differing results. This may be caused by differences in target site sensitivity, uptake and translocation effects or metabolism of the herbicides in the treated bacteria cells of the early test assays. Table 4.1.1 also presents physical and acute oral toxicity data [36, 37). 

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]. 

When comparisons are made between populations, both the effectiveness of the membrane barrier in R fish and the sensitivity of the target site can be demonstrated (Table V). When endrin Ss/Rs ratios are compared, the ratio is less than 1 this suggests that more insecticide is required to elicit symptoms in the R than in the S fish. 

PARP-1 in vitro. The insulator function of most of the same CTCF target sites was sensitive to the general PARP inhibitor 3-aminobenzamide. Collectively, these results support a role for PAR and PARP(s) in the activity of insulators, with an insulator-bound protein, possibly CTCF, as a target for PARylation. 

Data on the toxicokinetics of a substance can be very useful in the interpretation of toxicological findings, and may replace the use of some default extrapolation factors used in route-to-route (Section 5.5) or interspecies extrapolations (Section 5.3). In addition, interindividual differences in sensitivity to toxicants may be identified on the basis of toxicokinetic data, thereby making it possible to make the risk assessment more comprehensive by including sensitive subpopulations (Section 5.4). In conjunction with information on the relationship between concentration-dose at the target site and the toxic effect, toxicokinetic information may be an important tool for extrapolation from high to low dose effects. 

The GABAA receptor is now believed to be the major target site for anaesthetic action. The GABAA receptors exist as a family of subtypes with their pharmacology determined by their composition. GABAA receptors are pentameric and comprise of two a, two 3 (or 0), and one y (or s) subunits, which assemble to form a chloride-sensitive pore. When the receptor is activated, transmembrane chloride conductance increases, resulting in hyperpolarisation of the postsynaptic cell membrane and functional inhibition of the postsynaptic neurone. 

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