Aldehyde dehydrogenase of mice inhibited by thiocarbamate herbicides.
The herbicide S-ethyl N,N-dipropylthiocarbamate (EPTC) and three of its candidate metabolites (the sulfoxide, N-depropyl and S-methyl derivatives) inhibit mitochondrial low-Km aldehyde dehydrogenase (ALDH) in liver by 56 to 82% 2 hr after these thiocarbamates are administered intraperitoneally (ip) to mice at 8 mg/kg. They also greatly elevate the acetaldehyde level (determined as the O-benzyloxime ether) in blood (up to 500 microM) and brain (up to 3 ppm) 30 min after two ip treatments, the first with the thiocarbamate at 40 mg/kg and 2 hr later with ethanol at 1000 mg/kg. EPTC at 4 mg/kg inhibits liver ALDH activity by 50% and at 8 and 18 mg/kg gives half of the maximum ethanol-dependent elevation of acetaldehyde levels in blood and brain, respectively. The in vivo effects of other thiocarbamate herbicides at 8 mg/kg on ALDH activity and 40 mg/kg on acetaldehyde levels decrease in the order of thiobencarb, pebulate, vernolate and molinate > butylate and triallate >> cycloate. The percentage inhibition of liver ALDH activity generally correlates with the elevation in blood and brain acetaldehyde under these treatment protocols. B.W. Hart and M.D. Faiman (Biochem. Pharmacol. 43 403-406, 1992) have shown that the alcohol-aversion drug disulfiram is metabolized to S-methyl N,N-diethylthiocarbamate and its sulfoxide as the penultimate and ultimate metabolites inhibiting ALDH. Thus, the thiocarbamate herbicides and their metabolites are similar to the disulfiram metabolites not only in homologous structure but also in their potency range as ALDH inhibitors in vivo. On this basis some of the thiocarbamate herbicides may sensitize agricultural workers to ethanol intoxication.
Quistad
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Department of Environmental Science, Policy and Management, University of California, Berkeley 94720-3112.
Sparks
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Casida
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D000079:Acetaldehyde / Q000097:blood / Q000378:metabolism; D000444:Aldehyde Dehydrogenase / Q000037:antagonists & inhibitors*; D000818:Animals; D000431:Ethanol / Q000494:pharmacology; D006540:Herbicides / Q000633:toxicity*; D008297:Male; D051379:Mice; D008930:Mitochondria, Liver / Q000187:drug effects / Q000201:enzymology; D051381:Rats; D013859:Thiocarbamates / Q000633:toxicity*
D006540:Herbicides; D013859:Thiocarbamates; D000431:Ethanol; D000444:Aldehyde Dehydrogenase; D000079:Acetaldehyde