Thiocarbamate, metabolism

Metabolism of the Thiocarbamate Herbicide Molinate (Ordram) in Japanese Carp... 

Many organosulfur compounds undergo biological oxidation at the sulfur atom to yield products which have pronounced physiological activity or serve as intermediates in generating bioactive compounds. Three examples are the lachrymating agent in onions ( ) (1), the oxo intermediate ( ) in metabolic desulfuration of phosphorothionate insecticides to form potent cholinesterase inhibitors (2), and the sulfoxides QJ produced on metabolism of thiocarbamate herbicides (3). 

The herbicidal activity of -alkyl thiocarbamates (3-5) and the mutagenic activity of an -(2,3-dichloroallyl) thiocarbamate (6) are probably due to the reactivity or decomposition products of their metabolically-formed sulfoxides. 

Carbamylation Reactions. -Alkyl, -benzyl and -chloroallyl thiocarbamates do not readily react with GSH. In contrast, their sulfoxide derivatives ( and 6,) are very effective carbamylating agents for many thiols including GSH (19, ). The GSH conjugates formed vivo via 3 and 6 are quickly cleaved, acetylated and further metabolized as follows (19-21. 23. 24). 

Proherbicides. Thio- and dithiocarbamates probably require metabolic activation prior to exerting their herbicidal effects. Sulfoxide metabolites of the -alkyl thiocarbamates are generally more potent herbicides than the parent compounds ( -5). The herbicidal action of these sulfoxides probably results from their carbamylating action for thiols, although the specific target site or receptor is not defined (23, 24). It is conceivable that the -chloroallyl thiocarbamate herbicides may act in the same way, since their sulfoxides are also potent carbamylating agents... 

As in the case of propachlor mercapturic acid sulfoxide, the biological significance of xenobiotic mercapturic acids that contain oxidized sulfur is not known. Casida et al. (39) have reported that sulfoxidation of some thiocarbamate herbicides is a beneficial step in the detoxication process. However, cysteine conjugates can exhibit adverse biological activities. Smith (40) has reviewed work on the metabolism of the toxic principle in kale and has shown that C-S lyase action on S-methylcysteine sulfoxide produces the toxic principle. Virtanen ( ) has reviewed the processes in other plants that lead to the production of compounds with biological activity from -substituted cysteine sulfoxides. 

Oxidative desulfurization of the thiourea moiety is known to occur by an in vivo metabolism which forms the corresponding carbonyl compound, although there is no direct evidence for involvement of any activated oxygen species like superoxide, which is distributed widely in living cells. It was found that various thiocarbonyl derivatives such as thioureas, thioamides and thiocarbamates were readily desulfurized with 51 to the corresponding carbonyl compounds in almost quantitative yields at —35°C in CH3CN (equation 82). Desulfurization of thiourea with 02 was previously reported but the yields were comparatively low. ... 

Behki, R.M. (1995). Activation of atrazine metabolism thiocarbamate herbicides in Rhodococcus TE1. J. Environ. Sci. Health B-Pestic., 30 201-219. 

Thiocarbamate derivatives, (VI), effective as a4 integrin inhibitors having enhanced resistant to metabolism were prepared by Jackson (6) and used in treating diseases mediated by the binding interaction of a4 integrin such as inflammatory disorders. 

Modification of the Toxicity of Pesticides with Formulation Additives. Potentially the use of additives to modulate the toxicity of pesticides could lead to a considerable increase in their safety to non-target species, man included. This concept has been well explored and exploited in adding safeners to certain herbicides such as the thiocarbamates. These compounds stimulate defensive metabolic reactions in the crop species but not in weeds This principle has also been applied to vertebrates, but only to a very limited degree. Under some circumstances the thiocarbamate rice herbicide, molinate, may show toxicity to carp in nearby ponds. Based on a knowledge of the safeners that are active in plants, a compound was discovered that, when applied with molinate, acted as an antidote/safener for the carp (20). Little effort, either theoretical or empirical, seems to have gone into developing other such examples. 

Owing to its high volatility, molinate must be immediately incorporated into the soil after its application. Plants rapidly absorb molinate through their roots, from where it is translocated to the leaves. In the leaves of rice it is rapidly metabolised to COj and naturally occurring plant constituents, while in weeds this metabolism is slower. In the soil it is degraded by the microbial pathway. Its mode of action is unknown. At low rates it inhibits the development and growth of leaves. It presumably inhibits protein synthesis, as do the other thiocarbamates. 

Other bacterial CYPs also undertake the breakdown of carbon sources for microbial growth. For instance, CYP 108A1 (P450 gjjp) metabolizes ter-pineol , and CYPl 76A1 (P450 j J can metabolize cineol, while others can metabolize pollutants such as thiocarbamate herbicides and atrazine, as illustrated by CYPl 16 from a Rhodococcus sp. °. The CYP 105 family of streptomycetes especially is associated with a wide variety of xenobiotic... 

Tal, A., and Rubin, B. (1993). Metabolism of EPTC by a pure bacterial culture isolated from thiocarbamate-treated soil. Pestic. Sci. 39 207-212. 

GSTs in plants were first studied because of their ability to detoxify herbicides (30, 16). GST-based metabolism imparts herbicide tolerance in several plant species especially to the sulfonylureas, aryloxyphenoxypropionates, triazinone sulfoxides, and thiocarbamates herbicide families that are susceptible to GSH conjugation (16,31-35). There is a positive correlation of both GSH levels and the activity of specific GST enzymes wifti the rate of herbicide conjugation and detoxification (36-39). 

The chloracetamides and the thiocarbamates (chemical structure see Fig. 2) might also interfere with the metabolism of CoA. FLIrst (1987) proposed that the broad spectrum of effects such as inhibition of lipid, isoprenoid and flavonoid biosynthesis is caused by disrupting processes requiring CoA. 

In previous reviews [e.g. 1,3] I have described the action of three groups of herbicides on fatty acid metabolism. Thiocarbamates inhibit fatty acid elongation, substituted pyridazinones inhibit some desaturases while grass-specific herbicides have acetyl-CoA carboxylase as their target site. 

Figure 3.7. Structures of some thiocarbamates that affect lipid metabolism.

Various actions of thiocarbamates on lipid contents, lipid labeling, membrane constituents, and growth regulators have been reported (see Ref. 59). In addition, several antidotes or safeners which increase the tolerance of crop plants to thiocarbamates have been shown to reverse the effects of these herbicides on lipid metabolism. ... 

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