Metabolism of insecticidal methylcarbamates in animals

Abstract

The life of methylcarbamate insecticides in the animal body is very short. From 70 to 80% of an administered carbamate dose is usually eliminated, primarily in the urine, by 24 hr. The compounds are metabolized by hydrolytic and oxidative mechanisms and the resulting metabolites are excreted largely as sulfate and/or glucuronide conjugates. Some carbamates are reported to be conjugated directly, forming A-glucuronides, and then excreted.Hydrolysis of the carbamic acid ester results in detoxication of the insecticide. Carbamate metabolites formed by oxidation may be more or less toxic than the original compound. The toxicological properties of the conjugate metabolites have not been critically evaluated. This paper reviews recent findings on carbamate metabolism in animals, with particular emphasis on their metabolism by dairy cows and their residues in the milk.The toxicological significance of most foreign compounds entering the animal body is dependent, in part, on the manner in which they are metabolized. Some chemicals, such as strong bases, strong acids, and highly chlorinated hydrocarbons, are highly resistant to metabolism (Williams, 1963). These compounds, if toxic, would tend to retain their toxic action until excreted from the body. Usually, a chemical entering the body does undergo some type of transformation. The new chemical may be more toxic, less toxic, or equal in toxicity to the original compound. All three of these possibilities are known to occur as the result of metabolic transformation of certain carbamate insecticides by animal systems.The carbamate insecticides are esters of carbamic acid and those discussed herein are monomethyl derivatives of such esters. The first insecticidal carbamates synthesized were dimethyl carbamates (Gysin, 1952;Wiesmann, 1951;Wiesmann et al., 1951) but these did not have adequate insecticidal activity, and emphasis on the development of carbamate insecticides was placed on the more effective methylcarbamates (Casida, 1963;Fukuto, 1961;Kolbezen et al., 1954). The structures and chemical and common names of some of these compounds are given below.Although each of the compounds is a monomethyl carbamate, these three materials demonstrate that the carbamate insecticides are highly variable in their chemical makeup. Additional evidence as to the variability of the chemistry of this

Carboxylesterases in the Metabolism and Toxicity of Pesticides

“…Herein, the role of CarbEs can be crucial to reducing the in vivo toxicity of the carbamate because occasionally the oxidative metabolite can evidence greater toxicity than the parent compound. This is the case for 5-hydroxycarbaryl, which shows an acute oral LD 50 of 297 mg/kg to rats, whereas the LD 50 of carbaryl is 430 mg/kg (Dorough 1970).…”

Organophosphate and Carbamate Insecticides

“…Typical metabolic routes for OPs and carbamates are the cytochrome P450 routes, hydrolysis (enzymatic and nonenzymatic), and various conjugation mechanisms. 4,5 Distribution occurs throughout the body. The OPs tend to be more lipid soluble than carbamates.…”

The Metabolic Activation and Detoxication of Anticholinesterase Insecticides

“…The action of the N-methyl carbamates as anticholinesterases is described elsewhere in this volume. These insecticides, like the organophosphorus insecticides, are metabolically labile, and can be detoxified readily by either carboxylesterases, which can hydrolyze the carbamate linkage, or by the CYPs, which can oxidize various heteroatoms in the molecule leading to a variety of oxidized metabolites through ring or aliphatic oxidations (Dorough, 1970;Lin et al, 1975;Marshall and Dorough, 1977). These hydrolysis or oxidation products are amenable to Phase 2 metabolism, and therefore the metabolites can be readily excreted.…”