Carbamates selective toxicity

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. 

Pyrethrins and synthetic pyrethroids are among the safest of the topically applied ectoparasiticides, because of their selective toxicity for insects (mam-malian-to-insect toxic dose ratio is greater than 1000, compared with 33 for organophosphates and 16 for carbamate insecticides). In contrast to the very wide margin of safety for mammalian species, pyrethroids are toxic to fish. The synergistic action of pyrethrins and piperonyl butoxide (in combination preparations) is due to the inhibition by piperonyl butoxide of the microsomal enzyme system of some arthropods. Preparations of synthetic pyrethroids (permethrin, cypermethrin) often contain a mixture of drug isomers in varying proportions. 

Fahmy, M., Fukuto, T., Myers, R, and March, R. (1970). The selective toxicity of new IV-pho.sphorothioyl-carbamate esters. J. Agric. Food Chem. 18, 793-796,... 

Two dimensional polyacrylamide gel electrophoresis of helminth and mammalian tubulin revealed a difference in their a-subunits. This was confirmed by limited proteolytic peptide mapping where it was consistently observed that some peptides were novel to each tubulin.It was suggested that the difference in the cytoplasmic a-tubulin subunit described compared with that of mammalian cells could account for the selective toxicity of the benzimidazole carbamates without the need to postulate differential pharmacokinetics between parasite and host. 

Figure 12.63 provides another example of the diversity of metabolic processes to which pesticides are subjected after application. In the case of the carbamate insecticide carbaryl, the predominant processes are oxidation and hydrolysis, which maybe followed by conjugation of primary metabolites with glutathione. The character of metabolic transformations is closely related to the pesticide selectivity (toxicity) to target and non-target organisms. 

HPLC was used to determine that Gymnodimum catenatum was the causative organism in PSP outbreaks in Tasmania (77) and Spain (Sullivan, unpublished). G. catenatum produces a suite of toxins predominated by the low-toxicity sulfamate toxins. Cl to C4, and while shellfish feeding on G. catenatum contain predominantly these toxins, they also contain some carbamate and decarbamoyl toxins. Currently, it is not known if the carbamate and decarbamoyl toxins are present due to chemical conversion from the sulfocarbamoyl form or due to selective retention of trace quantities already present in the dinoflagellates. The HPLC played a key role in these studies by providing a rapid, quantitative means to differentiate the various toxins present. 

Carbamate, RNHCOOR, produced from carbonylation pathways can be selectively converted to isocyanate (1.4). Carbonylation pathways offer a number of advantages (i) the environmentally benign nature of the reactants, (ii) the high selectivity of the reaction processes, (iii) the stability and low toxicity of carbamate products and (iv) the wide range of applications of carbamate as chemical feedstock. 

The results of a comparative metabolism study of an aryl-sulfenyl derivative of carbofuran [2,2-dimethy1-2,3-dihydro-benzofuranyl-7 -methyl-N-(2-toluenesulfenyl)carbamate] in the house fly and white mouse Indicated the selective action of this compound to be a consequence of different metabolic pathways in insects and mammals (12). The arylsulfenyl group on the carbamate moiety allows the mammal to carry out metabolic reactions leading to less toxic products which are rapidly conjugated, while the toxic parent methylcarbamate is formed in the insect. 

Uncharged carbamates, such as carbaryl (8.20, sevin), can penetrate the CNS of insects (which do not use AChE in their neuromuscular junction) and they act quite selectively as insecticides with a low toxicity to mammals (median lethal dose [LDjg] in the rat = 540 mg/kg, p.o.). Many useful insecticides can thus be found in this group. Malathion (8.21) is a pro-drug, since the thiophosphate must be bioactivated to the phosphate form—a transformation carried out by insects but not mammals. Additionally, the ester groups of malathion are rapidly hydrolyzed in higher organisms to water-soluble and... 

In parallel to these studies, carbamate compounds 1 and 11-14 were assessed for their antitumor efficacy in mouse cancer xenograft models.15 When implanted human colon cancer CXF280 xenografts were grown within mice for fourteen days, doses of test compounds were administered orally. After a three-week regimen, excised tumor volumes were measured and the percent inhibition of tumor growth was calculated. From this investigation, capecitabine (1) was found to be the most effective treatment, and was furthermore found not to cause intestinal toxicity.16 All of these preclinical observations contributed to the selection of capecitabine as a candidate for further development. 

In summary, capecitabine (1), an A -carbamate pyrimidine nucleoside prodrug of cytotoxic antimetabolite 5-fluorouracil, is an FDA-approved anticancer drug that can be administered orally. This compound uses a multilayer of prodrug strategies that not only avoids side effects arising from exposure of toxic metabolites to healthy tissue but is converted to 5-fluorouracil only by enzymes preferentially expressed in many cancer cell types, thus resulting in selective delivery of the drug to tumors. Capecitabine is marketed under the trade name of Xeloda for use in the treatment of metastatic colorectal and breast cancers and metastatic breast cancer that is resistant to paclitaxel or anthracycline therapies. 

Why then, since such an abundance of metabolic inhibitors is available, do so few of them find practical application Examples are the folic acid reductase inhibitors, such as aminopterin, the purine and pyrimidine analogs used as cytostatics in cancer chemotherapy and known for their high toxicity in a wide variety of species, and the organic phosphates and carbamates used as insecticides but also highly toxic to mammals. Lack of selectivity in the action of metabolic inhibitors is inherent in their mechanism of action due to the universality of biochemical processes and principles throughout nature. Selectivity in action requires species differences in biochemistry. For the antivitamins, for instance, there is not only a lack of species differences in action in addition, the fact that vitamins often serve as cofactors for a variety of enzymes is a serious drawback to endeavors to obtain agents with species-selective action. 

Enzyme inhibitors may or may not be very selective, and their effects depend on the importance of the enzyme in different organisms. Plants lack a nervous system and acetylcholinesterase does not play an important role in other processes, whereas essential amino acids are not produced in animals. Glyphosate and other inhibitors of amino acid synthesis are therefore much less toxic in animals than in plants, and the opposite is true for the organophosphorus and carbamate insecticides. 

Many pesticides are esters or amides that can be activated or inactivated by hydrolysis. The enzymes that catalyze the hydrolysis of pesticides that are esters or amides are esterases and amidases. These enzymes have the amino acid serine or cysteine in the active site. The catalytic process involves a transient acylation of the OH or SH group in serin or cystein. The organo-phosphorus and carbamate insecticides acylate OH groups irreversibly and thus inhibit a number of hydrolases, although many phosphorylated or carbamoylated esterases are deacylated very quickly, and so serve as hydrolytic enzymes for these compounds. An enzyme called arylesterase splits paraoxon into 4-nitrophenol and diethyl-phosphate. This enzyme has cysteine in the active site and is inhibited by mercury(ll) salts. Arylesterase is present in human plasma and is important to reduce the toxicity of paraoxon that nevertheless is very toxic. A paraoxon-splitting enzyme is also abundant in earthworms and probably contributes to paraoxon s low earthworm toxicity. Malathion has low mammalian toxicity because a carboxyl esterase that can use malathion as a substrate is abundant in the mammalian liver. It is not present in insects, and this is the reason for the favorable selectivity index of this pesticide. 

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