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PubMed1998

[Studies on the biological effects of disulufiram--effect of an active metabolite of disulfiram on the activity of delta-aminolevulinic acid synthetase].

The effect of diethyldithiocarbamic acid methyl eater (Me-DDC), a metabolite of disulfiram, on hepatic delta-aminolevulinic acid (ALA) synthetase activity was investigated in male rats. The results obtained were as follows: 1) When rats were given intraperitoneally Me-DDC at the dose levels of 0.0625, 0.125, 0.25 and 0.50 mmol/kg, the activity of ALA synthetase showed a maximum level at a dose of 0.125 mmol/kg. 2) ALA synthetase activity increased rapidly and reached a maximum level in about 2 hr after the intraperitoneal administration of Me-DDC (0.125 mmol/kg). 3) Pretreatment with phenobarbital (an inducer of drug metabolizing enzymes) tended to depress the increase of ALA synthetase caused by Me-DDC, whereas pretreatment with SKF 525-A (an inhibitor of drug metabolizing enzymes) stimulated slightly the Me-DDC-induced increased of the enzyme. 4) The apparent Km value of the enzyme for glycine did not change but the Vmax value increased in Me-DDC-treated rats. 5) Actinomycin D (a potent inhibitor of DNA-dependent synthesis of RNA), when administered to rats before Me-DDC, completely prevented the induction of ALA synthetase caused by the latter compound. 6) Pretreatment with phorone (a glutathion depletor) 4 hr prior to the administration of Me-DDC completely inhibited the Me-DDC-induced increase of ALA synthetase.

5-Aminolevulinate Synthetase↗
PubMed2001

Metabolism of a disulfiram metabolite, S-methyl N,N-diethyldithiocarbamate, by flavin monooxygenase in human renal microsomes.

S-Methyl N,N-diethyldithiocarbamate (MeDDC), a metabolite of the alcohol deterrent disulfiram, is converted to MeDDC sulfine and then S-methyl N,N-diethylthiocarbamate sulfoxide, the proposed active metabolite in vivo. Several isoforms of CYP450 and to a lesser extent flavin monooxygenase (FMO) metabolize MeDDC in the liver. The human kidney contains FMO1 and several isoforms of CYP450, including members of the CYP3A, CYP4A, CYP2B, and CYP4F subfamilies. In this study the metabolism of MeDDC by the human kidney was examined, and the enzymes responsible for this metabolism were determined. MeDDC was incubated with human renal microsomes from five donors or with insect microsomes containing human FMO1, CYP4A11, CYP3A4, CYP3A5, or CYP2B6. MeDDC sulfine was formed at 5 microM MeDDC by renal microsomes at a rate of 210 +/- 50 pmol/min/mg of microsomal protein (mean +/- S.D., n = 5) and by FMO1 at 7.6 +/- 0.2 nmol/min/nmol (n = 3). Oxidation of 5 microM MeDDC was negligible by all CYP450 tested (< or =0.03 nmol/min/nmol). Inhibition of FMO by methimazole or heat diminished MeDDC sulfine formation 75 to 89% in renal microsomes. Inhibition of CYP450 in renal microsomes by N-benzylimidazole or antibody to the CYP450 NADPH reductase had no effect on MeDDC sulfine production. Benzydamine N-oxidation, a probe for FMO activity, correlated with MeDDC sulfine formation in renal microsomes (r = 0.951, p = 0.013). The K(M) values for MeDDC sulfine formation by renal microsomes and recombinant human FMO1 were 11 and 15 microM, respectively. These results demonstrate a role for the kidney and FMO1 in the metabolism of MeDDC in humans.

Chromatography, High Pressure Liquid↗
PubMed1977

Effects on rat liver acetaldehyde dehydrogenases in vitro and in vivo by coprine, the disulfiram-like constituent of Coprinus atramentarius.

Coprine, the disulfiram-like constituent of the mushroom Coprinus atramentarius was found to inhibit the low-Km dehydrogenase in rat liver and to increase the acetaldehyde level in blood during ethanol metabolism in vivo. Coprine did not inhibit the low-Km enzyme in vitro, but the hydrolytic product of coprine, 1-aminocyclo-propanol, was a potent inhibitor both in vitro and in vivo. A rapid onset of inhibition was observed after administration of coprine and the inhibition was long-lasting. It is suggested that 1-aminocyclopropanol is responsible for the inhibition caused by coprine in vivo.

Acetaldehyde↗