Oxidation of diethyldithiocarbamate to disulfiram by liver microsomal cytochrome P-450-containing monooxygenase system.
We examined the involvement of cytochrome P-450 in the oxidation of diethyldithiocarbamate (DTC) to disulfiram (DS) by liver microsomes in the presence of NADPH. DS difference spectra of liver microsomes showed a peak and trough at about 385 and 418 nm, respectively, which disappeared after further addition of glutathione (GSH). DTC alone had little effect on the microsomal spectrum, however, the addition of NADPH gradually produced a spectral change having a trough at 416-417 nm, which waned upon further addition of GSH. Microsomal DS production was increased by phenobarbital pretreatment and decreased by carbon tetrachloride pretreatment, depending on the activity of the cytochrome P-450-monooxygenase system. With microsomes peroxidized by cumene hydroperoxide, the extent of NADPH-dependent DS production lowered in proportion to the decrease in cytochrome P-450. Inhibitors of cytochrome P-450 such as SKF-525A, metyrapone and n-octylamine dose-dependently inhibited the DS production. Sodium azide, an inhibitor of catalase, increased the DS production, whereas addition of exogenous catalase only slightly suppressed it. It is concluded that oxidation of DTC to DS by liver microsomes largely proceeds via the cytochrome P-450-containing monooxygenase system and partly by hydrogen peroxide generated during NADPH oxidation.
Masuda
Y
Y
Toxicology Division, Niigata College of Pharmacy, Japan.
Nakamura
Y
Y
D000818:Animals; D002252:Carbon Tetrachloride Poisoning / Q000201:enzymology / Q000378:metabolism; D002374:Catalase / Q000037:antagonists & inhibitors / Q000494:pharmacology; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004221:Disulfiram / Q000378:metabolism*; D004050:Ditiocarb / Q000378:metabolism*; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology*; D006899:Mixed Function Oxygenases / Q000378:metabolism*; D010084:Oxidation-Reduction; D010634:Phenobarbital / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains
D003577:Cytochrome P-450 Enzyme System; D004050:Ditiocarb; D006899:Mixed Function Oxygenases; D002374:Catalase; D004221:Disulfiram; D010634:Phenobarbital