ALDEHYDE DEHYDROGENASE OF MICE INHIBITED BY THIOCARBAMATE HERBICIDES

The herbicide S-ethyl N,N-dipropylthiocarbamate (EPTC) and three of it s candidate metabolites (the sulfoxide, N-depropyl and S-methyl deriva tives) inhibit mitochondrial low-K-m, aldehyde dehydrogenase (ALDH) in liver by 56 to 82% 2 hr after these thiocarbamates are administered i ntraperitoneally tip) to mice at 8 mg/kg. They also greatly elevate th e acetaldehyde level (determined as the O-benzyloxime ether) in blood (up to 500 mu M) and brain (up to 3 ppm) 30 min after two ip treatment s, the first with the thiocarbamate at 40 mg/kg and 2 hr later with et hanol at 1000 mg/kg. EPTC at 4 mg/kg inhibits liver ALDH activity by 5 0% and at 8 and 18 mg/kg gives half of the maximum ethanol-dependent e levation of acetaldehyde levels in blood and brain, respectively. The in vivo effects of other thiocarbamate herbicides at 8 mg/kg on ALDH a ctivity and 40 mg/kg on acetaldehyde levels decrease in the order of t hiobencarb, pebulate, vernolate and molinate > butylate and triallate > > cycloate. The percentage inhibition of liver ALDH activity general ly correlates with the elevation in blood and brain acetaldehyde under these treatment protocols. B.W. Hart and M.D. Faiman (Biochem. Pharma col. 43 403-406, 1992) have shown that the alcohol-aversion drug disul firam is metabolized to S-methyl N,N-diethylthiocarbamate and its sulf oxide as the penultimate and ultimate metabolites inhibiting ALDH. Thu s, the thiocarbamate herbicides and their metabolites are similar to t he 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 et hanol intoxication.