Inhibition of rat liver low Km 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 Km mitochondrial aldehyde dehydrogenase (ALDH2, 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 ALDH2 in vivo. The dose of these thiocarbamates that inhibited rat liver ALDH2 by 50% (ID50) when administered 8 hr before determination of ALDH2, was found to be 5.2, 3.1, 1.6, 12, and 174 mg/kg, respectively. These thiocarbamates were ineffective rat liver ALDH2 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 ALDH2 in vitro. An equimolar dose of molinate and molinate sulfoxide inhibited rat liver ALDH2 in vivo to the same degree. Molinate-treated rats challenged with ethanol exhibited a disulfiram-like ethanol reaction. In conclusion, thiocarbamate herbicides inhibit ALDH2, probably due to the formation of their sulfoxide, and therefore have the potential to produce a disulfiram-like ethanol reaction in an unsuspecting population.
Department of Pharmacology and Toxicology, University of Kansas, Lawrence 66045.
B W
BW
Hart
M D
MD
Faiman
D000444:Aldehyde Dehydrogenase / Q000037:antagonists & inhibitors*; D000818:Animals; D004221:Disulfiram / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D000431:Ethanol / Q000378:metabolism; D006540:Herbicides / Q000737:chemistry / Q000633:toxicity*; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013859:Thiocarbamates / Q000737:chemistry / Q000633:toxicity*
D006540:Herbicides; D013859:Thiocarbamates; D000431:Ethanol; D000444:Aldehyde Dehydrogenase; D004221:Disulfiram