INHIBITION OF RAT-LIVER LOW K-M ALDEHYDE DEHYDROGENASE BY THIOCARBAMATE HERBICIDES - OCCUPATIONAL IMPLICATIONS

S-Methyl N,N-diethylthiolcarbamate (DETC-Me) is a metabolite formed during the bioactivation of disulfiram. The formation of its corresponding sulfoxide, S-methyl N,N-diethylthiolcarbamate sulfoxide (DETC-MeSO), from DETC-Me is required for low K-m mitochondrial aldehyde dehydrogenase (ALDH(2), EC 1.2.1.3) inhibition. DETC-Me is similar in structure to thiocarbamate herbicides with the general structure R1R2NC(O)SR3. Representative herbicides studied were n-propyl, n-propylthiocarbamate ethyl ester (EPTC), molinate, vernolate, ethiolate and butylate. All of these thiocarbamate herbicides inhibited rat liver ALDH(2) in vivo. The dose of these thiocarbamates that inhibited rat liver ALDH(2) by 50% (ID50) when administered 8 hr before determination of ALDH(2), was found to be 5.2, 3.1, 1.6, 12, and 174 mg/kg, respectively. These thiocarbamates were ineffective rat liver ALDH(2) inhibitors in vitro, unless rat liver microsomes and an NADPH-generating system were added to the incubation. The respective thiocarbamate sulfoxides were formed when the thiocarbamates were incubated with liver microsomes and an NADPH-generating system. The thiocarbamate sulfoxides all inhibited rat liver ALDH(2) in vitro. An equimolar dose of molinate and molinate sulfoxide inhibited rat liver ALDH(2) in vivo to the same degree. Molinate-treated rats challenged with ethanol exhibited a disulfiram-like ethanol reaction. In conclusion, thiocarbamate herbicides inhibit ALDH(2), probably due to the formation of their sulfoxide, and therefore have the potential to produce a disulfiram-like ethanol reaction in an unsuspecting population.