Esterases carbamate metabolism

Absorption of the quaternary carbamates from the conjunctiva, skin, and lungs is predictably poor, since their permanent charge renders them relatively insoluble in lipids. Thus, much larger doses are required for oral administration than for parenteral injection. Distribution into the central nervous system is negligible. Physostigmine, in contrast, is well absorbed from all sites and can be used topically in the eye (Table 7-4). It is distributed into the central nervous system and is more toxic than the more polar quaternary carbamates. The carbamates are relatively stable in aqueous solution but can be metabolized by nonspecific esterases in the body as well as by cholinesterase. However, the duration of their effect is determined chiefly by the stability of the inhibitor-enzyme complex (see Mechanism of Action, below), not by metabolism or excretion. 

Esters, amides, hydrazides, and carbamates can all be metabolized by hydrolysis. The enzymes, which catalyze these hydrolytic reactions, carboxylesterases and amidases, are usually found in the cytosol, but microsomal esterases and amidases have been described and some are also found in the plasma. The various enzymes have different substrate specificities, but carboxylesterases have amidase activity and amidases have esterase activity. The two apparently different activities may therefore be part of the same overall activity. 

Carbamates are substituted esters of carbamic acid (NH2COOH) with aliphatic or aromatic substituents on the oxygen and nitrogen atoms. Carbamate insecticides have an aryl or oxime N-methylcarbamate structure, and their mode of action is based on the inhibition of the enzyme acethylcholine esterase (1). However, this inhibition is reversible, and recovery from sublethal doses occurs rapidly. Some carbamate fungicides have a dithio, bisdithio, or benzimidazole carbamate basic structure, and dithiocarbamate fungicides inhibit the enzyme aldehyde deshydro-genase (2). The herbicides have an /V-alkylthiocarbamate or A-phenylcarbamate structure and interfere with photosynthetic activity or affect meristematic activity or lipid metabolism (3). Representative structures of carbamate pesticides are shown in Fig. 1. 

There are two types of esterases that are important in metabolizing insecticides, namely, carboxylesterases and phosphatases (also called phosphorotriester hydrolases or phosphotriesterases). Carboxylesterases, which are B-esterases, play significant roles in degrading organophosphates, carbamates, pyrethroids, and some juvenoids in insects. The best example is malathion hydrolysis, which yields both a- and (i-monoacids and ethanol (Figure 8.10). 

In similar studies, we have compared the toxicity of the same carbamate insecticide to several laboratory animal species that varied considerably insofar as rates of in vitro ester hydrolysis was concerned. Again, it was the more susceptible species which demonstrated the faster rates of hydrolysis (6). Neither absorption from the gut, or total metabolism as evidenced by excretion rates and metabolites excreted, was significantly different when the same carbamate was administered to either rats, mice, guinea pigs, or gerbils. At this point, it can only be surmised that the same properties that make the carbamates excellent in vivo inhibitors of acetylcholinesterase also make them excellent substrates for other esterases. 

Organophosphates (OPs), introduced in 1944, and carbamates, introduced in 1956, remain widely used and effective insecticides although not free from resistance problems. Metabolic resistance to OPs was reported 14 years after their introduction, compared to only 7 years for DDT and 5 for the carbamates. The complex metabolic fate of the OPs, including attack by cytochrome P-450 leading either to activation or detoxification, as well as by glutathione transferases and esterases, may play a role in this delay. Carbamates are not bioactivated they are detoxified by cytochrome P-450. 

FIG. 4. Metabolic. scheme for the oxidative and B-esterase metabolism of carbaryl to the ring and side chain hydroxylaied methyl carbamates and the major metabolite a-naphthol. 

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