Mammals selective toxicity

Dr. John E. Casida from the University of California Berkeley is inveshgating the fundamental basis for the selective toxicity of insecticides, including endosulfan, acting at the gamma-aminobutyric acid (GABA) receptor of mammals and insects. The research is sponsored by the National Institute of Environmental Health Sciences. 

Table 1 shows the ratios of LD50 values of various insecticidal components for mammals and insects, i.e., indexes for selective toxicity. 

Fukami, J-I., Shishido, T., Fukunaga, K. and Casida, J.E. Oxidative metabolism of rotenone in mammals, fish and insects and its relation to selective toxicity. J. Agr. Food. Chem. 

A few organophosphorus insecticides are also phosphoramidates, hydrolysis of the P-N bond being considered a route of detoxification. This is exemplified by the metabolism of acephate (9.82, Fig. 9.15), whose mechanisms of activation and detoxification have recently been re-examined in mice to better understand the relative innocuity of the compound in mammals and its selective toxicity in insects [156],... 

At the same time, these drugs do not bind to ribosomes in mammals, which is a reason for their selective toxicity. Macrolides can appear as bacteriostatics as well as bactericides depending on the concentration of the drug, sensitivity of the microorganisms, their growth rate, and as a matter of fact, the size of their colony. 

Hydrolytic reactions. There are numerous different esterases responsible for the hydrolysis of esters and amides, and they occur in most species. However, the activity may vary considerably between species. For example, the insecticide malathion owes its selective toxicity to this difference. In mammals, the major route of metabolism is hydrolysis to the dicarboxylic acid, whereas in insects it is oxidation to malaoxon (Fig. 5.12). Malaoxon is a very potent cholinesterase inhibitor, and its insecticidal action is probably due to this property. The hydrolysis product has a low mammalian toxicity (see chap. 7). 

The onset of symptoms depends on the particular organophosphorus compound, but is usually relatively rapid, occurring within a few minutes to a few hours, and the symptoms may last for several days. This depends on the metabolism and distribution of the particular compound and factors such as lipophilicity. Some of the organophosphorus insecticides such as malathion, for example (chap. 5, Fig. 12), are metabolized in mammals mainly by hydrolysis to polar metabolites, which are readily excreted, whereas in the insect, oxidative metabolism occurs, which produces the cholinesterase inhibitor. Metabolic differences between the target and nontarget species are exploited to maximize the selective toxicity. Consequently, malathion has a low toxicity to mammals such as the rat in which the LD50 is about 10 g kg-1. 

In the mid-1960s we showed firstly that the natural tolerance of houseflies to cyclodienes resulted mainly from oxidative detoxication (33 55) and secondly that another enzyme system, epoxide hydrase, converted certain dieldrin analogues into the corresponding trans-diols, (56,57) Interspecific differences in ability to attack enzymatically the unchlorinated ring systems of various analogues, either oxidatively and/or hydratively (if appropriate) can confer selective toxicity between insect species and also between insects and mammals (58) ... 

Selective toxicity to target organisms Since most antibiotics have selective toxicity to target organisms and low toxicity to mammals as shown in Table III, they can be safely used without harming man, livestock, fish and crops. Mode of action of agricultural antibiotics are summarized in Table XV. 

Note Since the enzyme is not found in mammals, inhibitors of this enzyme may be an effective means of controlling bacterial infection. Certainly, species-selective toxicity is an important consideration in the development of new antimicrobial agents. 

Carboxylesterases are responsible for the selective toxicity of malathion that favors mammals over insects. Carboxylesterase hydrolyzing trans-permethrin has been found in numerous insect species, including the fall armyworm, velvetbean caterpillar (Anticar-sia gemmatalis), cabbage looper (Trichoplnsia ni), tobacco budworm (Heliothis virescens), corn earworm (Helicoverpa zea), and spined soldier bug (Podisus maculwentris) (Yu, 1990). 

A good example of selective toxicity is illustrated in Figure 9.11. Malathion is a weakly active insecticide, whereas malaoxon is a strongly active insecticide. One of the main reasons why malathion is highly toxic to insects but not to mammals is that the latter have high carboxylesterase activities, which rapidly attack the two carboxylesters, but the... 

The CBs used as pesticides are N-substituted esters of carbamic acid. CBs developed in the 1950s as insect repellents were found to have insecticidal activity, leading to the development of the napthyl CBs with high anti-ChE activity and selective toxicity against insects. One example is carbaryl it is widely used because of its low toxicity to mammals and its degradability. Aldicarb, a plant systemic, is more toxic than carbaryl. A few years ago aldicarb was associated with a July 4th holiday incident when West Coast residents complained of anticholinergic symptoms after eating aldicarb-contaminated watermelon. 

Fig. 23. Malathion highly toxic to insects, less toxic to mammals. Note the high capacity to hydrolyse the carboxy ester moiety in mammals as compared to that in insects results in a selective toxicity for the latter...

The major inhibitory neurotransmitter in invertebrates is Y-aminobutyric acid (GABA). Inhibitory neurones are found both in the CNS and at the neuromuscular junction in invertebrates (1), whereas they are not found at the neuromuscular junction in mammals. The widespread distribution of GABA-ergic neurones in insects is probably partly responsible for the selective toxicity towards insects of certain commercial insecticides, e.g., cyclodienes (2-41. avermectin (5), and perhaps some pyrethroids ( ). 

The sulfonylurea herbicides are a new family of chemical compounds, some of which are selectively toxic to weeds but not to crops. The selectivity of the sulfonylureas results from their metabolism to non-toxic compounds by particular crops, but not by weeds. In addition to efficient weed control, the sulfonylurea herbicides provide environmentally desirable properties such as field use rates as low as two grams/hectare and very low toxicity to mammals. The high specificity of the herbicides for their molecular target contributes to both of these properties. In addition, the low toxicity to mammals results from their lack of the target enzyme for the herbicides. Sulfonylureas inhibit the enzyme acetolactate synthase (ALS), also known as acetohydroxyacid synthase (AHAS), which catalyzes the first common step in the biosynthesis of the branched chain amino acids leucine, isoleucine and valine. In mammals these are three of the essential amino acids which must be obtained through dietary intake because the biosynthetic pathway for the branched chain amino acids is not present. The prototype structure of a sulfonylurea herbicide is shown in Figure 1. 

Ryanodine-type compounds act primarily at the Ca2+ release channel in both mammals and insects [12], Ryanodol-type compounds, however, are more selective toxicants for insects than they are for mammals, suggesting a different mode of action for these compounds [13, 14]. 

Chemotherapeutic treatments rely dominantly on selective toxicity approaches targetted at killing the invader without killing the host. Albert distinguishes three selectivity principles favourable differences in drug distribution, favourable differences in biochemistry and favourable differences in cell structure. Certainly the most seducing of them are the differences in biochemistry. A practical application is the inhibition of the bacterial cell wall construction by p-lactam antibiotics, the activity is absolutely restricted to the bacteria s, just because similar cell walls do not exist in mammals. 

Rotenone (32) is known as potent insecticide, with reduced toxicity to mammals the oral acute LD50 in rats is 60 mg/kg, while intravenous and intraperitoneal LD50 values are 0.2 mg/kg and 1.6 mg/kg respectively [62]. Chronic studies indicated that the no observed effect level (NOEL) determined in rats in a 24-month exposure was 7.5 mg/kg of diet [114]. Results of this study and other previously reported suggest that even unusually high treatment rates of rotenone do not cause tumors or reproductive problems in humans [114]. Rotenone insecticide action is due to its ability to block oxidative phosphorylation in the mitochondria [62]. Selective toxicity to insects and not to mammals results from the existing differences in the inability of insects to further metabolize toxic rotenolones biodegradation products [63]. 

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