NADPH-dependent, regioselective S-oxidation of a thionosulfur- and thioether-containing xenobiotic, diethyldithiocarbamate methyl ester by rat liver microsomes.
The present study describes the NADPH-dependent, regioselective oxidation of diethyldithiocarbamate methyl ester (DDTC-Me), a dithiocarbamate ester containing both a thionosulfur (C = S) and a thioether (S-CH3) group, to two novel S-oxidized metabolites. DDTC-Me is a key metabolite in the overall bioactivation pathway for the clinically used alcohol deterrent, disulfiram. Incubation of DDTC-Me with rat liver microsomes resulted in the formation of two major metabolites. These metabolites were identified as DDTC-Me sulfoxide [S(O)CH3] and DDTC-Me sulfine (C = S+-O-) based on their NMR spectra and by MS. The formation of DDTC-Me sulfoxide was completely inhibited by the cytochrome P-450 inhibitors, emulgen 911 and 1-benzylimidazole, but only partially inhibited by heat inactivation of the flavin-containing moonooxygenases (FMO). This suggested that DDTC-Me sulfoxide formation is primarily catalyzed by cytochrome P-450 with a minor contribution from FMO. In contrast, the formation of DDTC-Me sulfine was inhibited from 60 to 80% in the presence of emulgen 911 and 1-benzylimidazole and 30 to 50% by heat inactivation of FMO, suggesting a partial role of FMO in the formation of DDTC-Me sulfine. DDTC-Me sulfoxide is a new class of dithiocarbamates that has not been previously described, whereas, DDTC-Me sulfine belongs to a class of thionosulfur sulfines that have been implicated in a number of toxicological processes.
Department of Pharmacology and Toxicology, University of Kansas, Lawerence 66045.
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D000444:Aldehyde Dehydrogenase / Q000037:antagonists & inhibitors*; D000818:Animals; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004050:Ditiocarb / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism*; D009249:NADP / Q000378:metabolism*; D010084:Oxidation-Reduction; D010105:Oxygenases / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013454:Sulfoxides / Q000378:metabolism; D015262:Xenobiotics / Q000493:pharmacokinetics*
D065607:Cytochrome P-450 Enzyme Inhibitors; D013454:Sulfoxides; D015262:Xenobiotics; D009249:NADP; C016571:methyl diethyldithiocarbamate; D003577:Cytochrome P-450 Enzyme System; D004050:Ditiocarb; D010105:Oxygenases; C020066:dimethylaniline monooxygenase (N-oxide forming); D000444:Aldehyde Dehydrogenase