dicumarol and Hemolysis

The enzyme DT-diaphorase mediates the two-electron reduction of quinones to hydroquinones. It has previously been shown that the toxicity of 2-methyl-1,4-naphthoquinone to rats is decreased by pre-treatment of the animals with compounds that increase tissue levels of this enzyme. In contrast, the severity of the haemolytic anaemia induced in rats by 2-hydroxy-1,4-naphthoquinone was increased in animals with high levels of DT-diaphorase. In the present experiments, the effect of alterations in tissue diaphorase activities on the toxicity of a third naphthoquinone derivative, 2,3-dimethyl-1,4-naphthoquinone, has been investigated. This compound induced severe haemolysis and slight renal tubular necrosis in control rats. Pre-treatment of the animals with BHA, a potent inducer of DT-diaphorase, diminished the severity of the haemolysis induced by this compound and abolished its nephrotoxicity. Pre-treatment with dicoumarol, an inhibitor of this enzyme, caused only a slight increase in the haemolysis induced by 2,3-dimethyl-1,4-naphthoquinone, but provoked a massive increase in its nephrotoxicity. Modulation of DT-diaphorase activity in animals may therefore not only alter the severity of naphthoquinone toxicity, but also cause pronounced changes in the site of toxic action of these substances. The factors that may control whether induction of DT-diaphorase in animals will decrease or increase naphthoquinone toxicity are discussed.

Topics: Administration, Oral; Animals; Butylated Hydroxyanisole; Dicumarol; Female; Hemolysis; Kidney Tubules; NAD(P)H Dehydrogenase (Quinone); Naphthoquinones; Necrosis; Oxidation-Reduction; Rats; Rats, Sprague-Dawley

The enzyme DT-diaphorase catalyses the 2-electron reduction of quinones. This reaction may facilitate the detoxification of such compounds, since the hydroquinone so formed can be converted into non-toxic conjugates. There is evidence for the involvement of DT-diaphorase in the detoxification of menadione (2-methyl-1,4-naphthoquinone) in a wide range of cells and tissues in vitro, but no information is available on the possible influence of this enzyme on the harmful effects of menadione in vivo. In animals, menadione is selectively toxic to erythrocytes, causing haemolytic anaemia. In the present study, rats were treated with dicoumarol, an inhibitor of DT-diaphorase, or butylated hydroxyanisole (BHA), a substance that increases the activity of this enzyme in vivo. They were then challenged with a toxic dose of menadione. Dicoumarol increased the severity of menadione-induced haemolytic anaemia while BHA decreased it, consistent with a role for DT-diaphorase in the detoxification of menadione in vivo, as previously described in vitro.

Topics: Anemia, Hemolytic; Animals; Antioxidants; Butylated Hydroxyanisole; Dicumarol; Dihydrolipoamide Dehydrogenase; Enzyme Inhibitors; Erythrocytes; Female; Heinz Bodies; Hemolysis; Hemostatics; Liver; NAD(P)H Dehydrogenase (Quinone); Organ Size; Rats; Rats, Sprague-Dawley; Spleen; Vitamin K

Topics: Adult; Aged; Aortic Valve; Aortic Valve Insufficiency; Aortic Valve Stenosis; Aortography; Blood Flow Velocity; Blood Pressure; Dicumarol; Female; Follow-Up Studies; Haptoglobins; Heart Valve Prosthesis; Hemolysis; Humans; L-Lactate Dehydrogenase; Male; Middle Aged; Postoperative Complications; Prognosis; Recurrence; Thromboembolism

Topics: Anti-Inflammatory Agents; Aspirin; Blood Platelets; Cell Membrane; Chloroquine; Coumarins; Depression, Chemical; Dicumarol; Erythrocytes; Fibrinolysis; Flufenamic Acid; Hemolysis; Humans; Hypotonic Solutions; In Vitro Techniques; Indomethacin; Inflammation; Mefenamic Acid; Oxyphenbutazone; Phenylbutazone; Phenylpropionates; Platelet Adhesiveness; Pyrazoles; Receptors, Drug; Structure-Activity Relationship

Topics: Adenosine Diphosphate; Animals; Blood Coagulation Tests; Blood Platelets; Cell Membrane; Cell Membrane Permeability; Coumarins; Densitometry; Dicumarol; Electric Conductivity; Erythrocytes; Guinea Pigs; Hemolysis; Injections, Intravenous; Osmotic Fragility; Platelet Adhesiveness; Premedication; Prothrombin Time; Rabbits; Rats; Thrombosis; Time Factors