In vivo and in vitro effects of thiuram disulfides and dithiocarbamates on hepatic microsomal drug metabolism in the rat*1

Zemaitis, Michael A.; Greene, Frank E.

doi:10.1016/0041-008x(79)90041-3

Cited by 54 publications

(18 citation statements)

References 20 publications

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“…Previous investigations have shown that dithiocarb depresses the activity of the microsomal drug-metabolizing mono-oxygenase system in vitro (7,5,8,9). Our results show that this effect occurs in vivo.…”

Section: Discussionsupporting

confidence: 69%

“…As the microsomal mono-oxygenase system is involved in the metabolic activation of these hepatotoxic agents, we postulated that dithiocarb exerted its antihepatotoxic effects by depressing the activity of this microsomal drug-metabolizing system. Several investigations have shown that dithiocarb has an inhibitory effect on the microsomal rnono-oxygenases in vitro (7,5,8,9). This study investigates whether dithiocarb, at a hepatoprotective dose level, was able to alter the pharmacokinetics of hepatotoxic drugs and chemicals in vivo.…”

Section: Introductionmentioning

confidence: 99%

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Effect of diethyldithiocarbamate on the metabolic elimination of hexobarbital, phenazone, tolbutamide and four halogenated hydrocarbons

Siegers

Biltz

Pentz

1981

European Journal of Drug Metabolism and Pharmacokinetics

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The present study describes the inhibitory effects of diethyldithiocarbamate (dithiocarb) on the metabolic elimination of hexobarbital, phenazone, tolbutamide and four halogenated hydrocarbons. The plasma half-life for the beta-slopes of hexobarbital (25 mg/kg, i.v.) and phenazone (50 mg/kg, i.v.) were increased 2.5 and 3.5 fold respectively, when dithiocarb (100 mg/kg, i.p.) was administered simultaneously. The plasma half-life of tolbutamide was 2.27 h, when administered alone to rats; and 4.04 h, when administered with dithiocarb. Metabolic elimination of halothane, trichloroethylene, dichloroethane, and carbon tetrachloride, from the atmosphere of a closed exposure system was studied in rats. Treatment with dithiocarb (100 mg/kg, i.p.) immediately before exposure, prolonged the elimination half-life of: halothane (103 parts/10(6)) by a factor of 7.6, of trichloroethylene (25 parts/10(6)) by a factor of 5.3; dichloroethane (69 parts/10(6)) by 4.6; and carbon tetrachloride (38 parts/10(6)) by 2.4, respectively. The inhibitory actions of dithiocarb on the metabolism of the tested drugs and chemicals are explained as the consequences of a depressed microsomal mono-oxygenase activity due to a decrease in the cytochrome P 450 content.

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Section: Discussionsupporting

confidence: 69%

Section: Introductionmentioning

confidence: 99%

Effect of diethyldithiocarbamate on the metabolic elimination of hexobarbital, phenazone, tolbutamide and four halogenated hydrocarbons

Siegers

Biltz

Pentz

1981

European Journal of Drug Metabolism and Pharmacokinetics

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“…Dopamine [3-hydroxylase, aldehyde dehydrogenase and glutathione peroxidase (7,10,16) may be inhibited, but such could not increase the amount of H202 reaching catatase in our experiments. DDC, also a metabolite of disulfiram might inhibit the drug metabolizing system (cytochrome P450), which is another source of H20 2 (62,64,66). But phenelzine, which also inhibits the microsomal oxidative drug metabolism of rat liver (4), does not alter the RCA in our experiments.…”

Section: Conditions (At + Methanol)mentioning

confidence: 68%

Myocardial H2O2 production in the unanaesthetized rat Influence of fasting, myocardial load and inhibition of superoxide dismutase and monoamine oxidase

Kerckaert

Roels

1986

Basic Res Cardiol

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Myocardial H2O2 production was studied by means of the in vivo administration of aminotriazole (AT), which inactivates the catalase-H2O2 complex compound I. Measurements of the residual catalase activity in male and female rats indicate that beta-oxidation of fatty acids in peroxisomes does not contribute in a substantial way to energy production in response to fasting or to an increased myocardial load, despite previous data on peroxisomes in myocardium. Superoxide dismutase (SOD) inhibition by diethyldithiocarbamate demonstrates that SOD participates in the production of H2O2 in physiological conditions. Such a role was not demonstrated for monoamine oxidase through inhibition by phenelzine.

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“…DCs have thus been reported to inhibit enzymes by covalent interaction to free protein thiols (2,5) as well as to oxidize glutathione through a glutathione peroxidase-like activity (6,7). DCs may also interfere with cellular detoxication mechanisms as they are reported to suppress hepatic microsomal drug metabolism (8) and to inhibit glutathione S-transferases (9). In addition, the diethyldithiocarbamate (DDC) derivative has been found to inhibit copper/ zinc superoxide dismutase activity by withdrawal of essential metal from the enzyme (10,11) and to deplete intracellular glutathione in a non-superoxide dismutase-dependent manner (12,13).…”

mentioning

confidence: 99%

Dithiocarbamates Induce Apoptosis in Thymocytes by Raising the Intracellular Level of Redox-active Copper

Nobel

Kimland

Lind

et al. 1995

Journal of Biological Chemistry

269

208

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Dithiocarbamates are metal-chelating compounds that can exert either pro-oxidant or antioxidant effects in different situations. They have recently been found to potently inhibit apoptotic cell death, an activity attributed to their antioxidant action. However, when thymocytes were exposed to pyrrolidine dithiocarbamate, an oxidation of the glutathione pool occurred within 90 min. Longer incubation resulted in cell shrinkage, chromatin fragmentation, glutathione depletion, and eventual cell lysis, which is typical of apoptosis in these cells. These changes were inhibited by inclusion of non-permeable metal chelators in the incubation medium, suggesting that pyrrolidine dithiocarbamate exerts its toxic effect by transporting a redox-active metal into the cell. This was directly confirmed when sustained 8-fold elevations of intracellular copper were detected after addition of pyrrolidine dithiocarbamate. In agreement with this, supplementation of the incubation medium with submicromolar concentrations of copper significantly potentiated pyrrolidine dithiocarbamate toxicity. We conclude that pyrrolidine dithiocarbamate exerts a powerful pro-oxidant effect on thymocytes due to its ability to transport external redox-active copper into cells. The resulting increase in glutathione disulfide may also explain the temporary anti-apoptotic activity of this compound described in other systems.

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In vivo and in vitro effects of thiuram disulfides and dithiocarbamates on hepatic microsomal drug metabolism in the rat*1

Cited by 54 publications

References 20 publications

Effect of diethyldithiocarbamate on the metabolic elimination of hexobarbital, phenazone, tolbutamide and four halogenated hydrocarbons

Effect of diethyldithiocarbamate on the metabolic elimination of hexobarbital, phenazone, tolbutamide and four halogenated hydrocarbons

Myocardial H2O2 production in the unanaesthetized rat Influence of fasting, myocardial load and inhibition of superoxide dismutase and monoamine oxidase

Dithiocarbamates Induce Apoptosis in Thymocytes by Raising the Intracellular Level of Redox-active Copper

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