S-methyl N,N-diethylthiolcarbamate sulfone, an in vitro and in vivo inhibitor of rat liver mitochondrial low Km aldehyde dehydrogenase.
S-Methyl N,N-diethylthiolcarbamate sulfone (DETC-Me sulfone) was investigated for its rat liver mitochondrial low Km aldehyde dehydrogenase (ALDH2) inhibitory properties. DETC-Me sulfone inhibited ALDH2 in vitro (IC50 = 3.8 microM) and in vivo (ID50 = 170 mumol/kg; 31 mg/kg). Maximum inhibition (60%) of ALDH2 was observed 8 hr after DETC-Me sulfone administration. In addition, incubation of S-methyl N,N-diethylthiolcarbamate (DETC-Me) or S-methyl N,N-diethylthiolcarbamate sulfoxide (DETC-Me sulfoxide) with rat liver microsomes and an NADPH-generating system failed to produce DETC-Me sulfone. Furthermore, DETC-Me sulfone could not be detected in plasma from rats treated with either DETC-Me sulfoxide or DETC-Me sulfone. In conclusion, DETC-Me sulfone inhibited ALDH2 in vitro and in vivo. However, there was no evidence suggesting that DETC-Me sulfoxide was metabolized to DETC-Me sulfone.
Nagendra
S N
SN
Department of Pharmacology and Toxicology, University of Kansas Lawrence 60045.
Madan
A
A
Faiman
M D
MD
D000444:Aldehyde Dehydrogenase / Q000037:antagonists & inhibitors*; D000818:Animals; D004221:Disulfiram / Q000378:metabolism; D004050:Ditiocarb / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D008297:Male; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000201:enzymology; D010084:Oxidation-Reduction; D051381:Rats; D013859:Thiocarbamates / Q000378:metabolism
C087204:S-methyl-N,N-diethylthiolcarbamate sulfone; D013859:Thiocarbamates; C073220:S-methyl N,N-diethylthiolcarbamate sulfoxide; C070631:S-methyl diethylthiocarbamate; D004050:Ditiocarb; D000444:Aldehyde Dehydrogenase; D004221:Disulfiram