S-methylation as a bioactivation mechanism for mono- and dithiocarbamate pesticides as aldehyde dehydrogenase inhibitors.
S-Methylation is a new bioactivation mechanism for metam and metabolites of methyl isothiocyanate and dazomet in mice. These soil fumigants are converted to S-methyl metam [MeNHC(S)SMe] which reaches peak levels in liver, kidney, brain, and blood 10-20 min after intraperitoneal (ip) treatment. The half-life of S-methyl metam administered ip is 8-12 min in each of these tissues. S-Methyl metam-oxon [MeNHC(O)SMe] is also detected as a metabolite of each of these soil fumigants on analysis by gas chromatography/mass spectrometry with chemical ionization. The conversion of methyl isothiocyanate to S-methyl metam and its oxon probably involves conjugation with glutathione, hydrolysis to S-(N-methylthiocarbamoyl)-cysteine, cleavage by cysteine conjugate beta-lyase to release metam, and finally methylation and oxidative desulfuration. Metam and dazomet are converted to S-methyl metam by mouse liver microsomes on fortification with S-adenosylmethionine. Metam, methyl isothiocyanate, dazomet, and three metabolites (metam-oxon [MeNHC(O)SH], MeNHC(S)SMe, and MeNHC-(O)SMe) administered ip to mice at 40 mg/kg inhibit low-Km liver mitochondrial aldehyde dehydrogenase and elevate ethanol-dependent blood and brain acetaldehyde levels. Several fungicides including the dialkyldithiocarbamates as the disulfide (thiram and the related alcohol-abuse drug disulfiram) and metal salts (ziram) also yield S-methyl thiocarbamate metabolites. Eight S-alkyl and S-(chloroallyl) thiocarbamate herbicides (EPTC, molinate, butylate, vernolate, pebulate, diallate, sulfallate, and triallate), but not their S-chlorobenzyl analog (thiobencarb), undergo sequential liberation of the thiocarbamic acid and then S-methylation, forming the S-methyl thiocarbamates which are new metabolites and potential aldehyde dehydrogenase inhibitors. The S-methyl mono- and dithiocarbamate metabolites of these herbicides and fungicides are easily identified by retention time on gas chromatography and by mass spectrometry giving [MH]+ plus [R1R2NCO]+ or [R1R2NCS]+, respectively, as the two major ions.
Staub
R E
RE
Department of Environmental Science, Policy and Management, University of California, Berkeley 94720-3112, USA.
Sparks
S E
SE
Quistad
G B
GB
Casida
J E
JE
D000444:Aldehyde Dehydrogenase / Q000037:antagonists & inhibitors*; D000818:Animals; D001711:Biotransformation; D000431:Ethanol / Q000378:metabolism; D008401:Gas Chromatography-Mass Spectrometry; D005978:Glutathione / Q000378:metabolism; D006540:Herbicides / Q000378:metabolism*; D017879:Isothiocyanates / Q000378:metabolism*; D008297:Male; D008745:Methylation; D051379:Mice; D013829:Thiadiazines / Q000378:metabolism*
D006540:Herbicides; D017879:Isothiocyanates; D013829:Thiadiazines; D000431:Ethanol; D000444:Aldehyde Dehydrogenase; D005978:Glutathione; C005227:methyl isothiocyanate; C012864:dazomet