Diallate, triallate, and sulfallate herbicides: identification of thiocarbamate sulfoxides, chloroacroleins, and chloroallylthiols as mouse microsomal oxidase and glutathione S-transferase metabolites

Triallate was administered orally to Sprague-Dawley rats. Twelve excreted metabolites were identified, the most abundant being 2,3,3-trichloro-2-propenesulfinic acid. Five metabolites derived from 2,3,3-trichloro-2-propenethiol were identified in excreta, including a methyl sulfone mercapturate whose structure was confirmed by X-ray crystallography. Three 2-chloroacrylate metabolites were identified, including a 2-chloroacrylate mercapturate whose structure was confirmed by X-ray crystallography. 2,3,3-Trichloro-2-propenol and hydroxytriallate were also identified as metabolites. Dosing of radiolabeled thiol and sulfinic acid to separate animals resulted in excretion of only thiolderived metabolites in the urine of thiol-dosed rats, while sulfinic acid and sulfonic acid were excreted by sulfinic acid-dosed rats. Triallate metabolism in rats proceeds via three main pathways, i.e., S-oxidation leading to sulfur acids, S-oxidation/hydrolysis/reduction leading to thiol derivatives, and C-oxidation of the 2,3,3-trichloropropenethioI moiety. This study demonstrates that formation of readily excreted sulfur acids and thiol derivatives is the major route of triallate metabolism in rats.

Section: Resultsmentioning

confidence: 95%

Section: Resultsmentioning

confidence: 99%

Metabolism of triallate in Sprague-Dawley rats. 2. Identification and quantitation of excreted metabolites

Nadeau¹,

Chott²,

Fujiwara³

et al. 1993

“…Thiol 4 was a minor metabolite produced in S-9 and microsomal incubations. Addition of GSH to incubations increased the formation of metabolite 4, possibly via reaction of GSH with the transient sulfoxide 5 described below (Mair and Casida, 1991) or via antioxidant activity of GSH. Thiol 4 was formed early in the course of microsomal and S-9 incubations and was then consumed, most likely via oxidation to the sulfur acids 2 and 3.…”

Section: Resultsmentioning

confidence: 99%

“…Sulfinic acid 2 is the major product of in vitro triallate breakdown under oxidative conditions. Metabolite 2 likely arises via initial oxidation of triallate to sulfoxide 5 (Scheme I), followed by hydrolysis to the rapidly oxidized sulfenic acid 21 (Mair and Casida, 1991).…”

Section: Discussionmentioning

confidence: 99%

Metabolism of triallate in Sprague-Dawley rats. 3. In vitro metabolic pathways

Hackett¹,

Kotyk²,

Fujiwara³

et al. 1993

Rat liver enzyme preparations were used to investigate the mechanistic pathways of triallate metabolism. Incubation of [14C]triallate with NADPH-fortified microsomes gave rise to metabolites generated via a number of reaction types, including sulfur oxidation/hydrolysis and hydroxylation of the allylic thiol moiety accompanied by rearrangement. Addition of glutathione (GSH) to microsomal incubations resulted in the formation of GSH conjugates arising via conjugate addition of glutathione to metabolic intermediates such as trichloroacrolein. Addition of GSH to microsomal incubations inhibited the binding of triallate-derived radioactivity to microsomal proteins. Metabolite identification was accomplished by mass spectrometry and chemical synthesis and by a novel application of heteronuclear multiple quantum coherence (HMQC) NMR spectroscopy. Elucidation of the in vitro metabolism of triallate provides important mechanistic information regarding triallate metabolism in the laboratory rat.

“…Haloalkyl and haloallyl substituents help optimize or increase the potency of several pesticide chemotypes. The thiocarbamate herbicide diallate, 6C , is oxidized to the sulfoxide, which undergoes [2,3]sigmatropic rearrangement and 1,2-elimination reactions to yield 2-chloroacrolein, an exceptionally potent mutagen and known carcinogen. − Nematicides trichloropropane and dibromochloropropane (DBCP) undergo methylene hydroxylation, which yields reactive intermediates that dehydrohalogenate spontaneously to 2-chloroacrolein and the even more potent mutagen 2-bromoacrolein. − Diallate and DBCP are no longer used due to unacceptable mutagenic and carcinogenic activity.…”

Section: Thiocarbamate Sulfoxidesmentioning

confidence: 99%

Unexpected Metabolic Reactions and Secondary Targets of Pesticide Action

Casida

2016

Self Cite

Pesticides provide a fascinating combination of substituents not present in other environmental chemicals, leading to unexpected metabolites and toxicological effects in pests, mammals, and other organisms. The parent compound and/or metabolites of some pesticides have multiple targets, requiring identification of the causal agents and their modes of action. This review considers a few of the author's observations in the past six decades, some solved and others still puzzling. It illustrates that a new substituent combination not only confers specific chemical and physical properties to a class of compounds but often yields metabolites with a surprising variety of biological activities. Examples considered include proinsecticides, procyclic phosphates, CYP inhibitors as synergists, thiocarbamate sulfoxides, promutagens, carcinogens, and hepatotoxins, and stress tolerance inducers in plants. Although the discoveries considered are based on pesticide toxicology, they are broadly applicable to environmental toxicology and xenobiotics in animals, plants, and microorganisms.