dicumarol and Liver-Diseases

Topics: Aminosalicylic Acids; Animals; Ataxia; Cats; Chlordan; Cycloserine; DDT; Dicumarol; Disulfiram; Enzyme Induction; Female; Genetics, Medical; Humans; Intestinal Absorption; Isoniazid; Kinetics; Liver Diseases; Male; Metabolism; Microsomes, Liver; Nystagmus, Pathologic; Pedigree; Pharmacogenetics; Phenobarbital; Phenytoin; Rats; Thiazines

The role of NAD(P)H:quinone reductase (QR; EC 1.6.99.2) in the alcohol-derived protective effect against hepatotoxicity caused by acetaminophen (APAP) was studied. In mice pretreated with dicoumarol (30 mg/kg), an inhibitor of QR, hepatic necrosis caused by APAP (400 mg/kg) was potentiated. Hepatocellular injuries induced by APAP, as assessed by liver histology, serum aminotransferase activities, hepatic glutathione (reduced and oxidized) contents, and liver microsomal aminopyrine N-demethylase activities, all were potentiated by pretreatment of mice with dicoumarol. Even in mice given APAP and ethanol (4 g/kg), in which APAP-inducible hepatic necrosis was abolished, the dicoumarol pretreatment again produced moderate hepatotoxicity and reversed the protective effect of ethanol. In mice pretreated with dicoumarol and ethanol, levels of APAP in blood and bile fluid between 90 and 240 min were higher than those in mice given ethanol. However, the biliary contents of sulfate and glucuronide conjugates of APAP were much lower than those in the ethanol group, particularly at early time points. In contrast, the biliary level of APAP-cysteine conjugate, which in the ethanol group was at its basal level, was increased maximally in the dicoumarol-pretreated mice. In the mice given dicoumarol and ethanol, the biliary APAP-cysteine conjugate level was increased moderately. These results suggest that ethanol inhibited not only the microsomal (CYP2E1 mediated) formation of a toxic quinone metabolite from APAP, but also accelerated the conversion of the toxic quinone metabolite produced back to APAP by stimulating cytoplasmic QR activity. In the presence of dicoumarol, however, QR activity was inhibited, and conversion of the toxic quinone metabolite back to APAP became inhibited and diminished the alcohol-dependent protective effect against APAP-induced hepatic injury.

Topics: Acetaminophen; Alcohol Dehydrogenase; Aminopyrine N-Demethylase; Analgesics, Non-Narcotic; Animals; Chemical and Drug Induced Liver Injury; Dicumarol; Enzyme Inhibitors; Ethanol; Glutathione; Liver; Liver Diseases; Male; Mice; Mice, Inbred ICR; Microsomes, Liver; Protective Agents; Quinone Reductases; Transaminases

The conversion of prothrombin by ecarin is independent of the presence of gamma carboxyglutamic residues on the N terminal of the molecule. Ecarin converts therefore also the acarboxylated precursor-PIVKA II. In a group of 347 patients under dicoumarol therapy of different intensity and duration PIVKA was detected in BaSO4 adsorbed PPP only in samples where prothrombin level (Quick's test) was lower than 50% of normal values. Increase in PIVKA did not correspond to the decrease of prothrombin. In some cases where the treatment was longer than two years no PIVKA was detected even when prothrombin was under 20%. This is explained by synthesis of partially carboxylated prothrombin molecules, which can be adsorbed. In liver diseases the ecarin test and Quick's time in native, untreated PPP showed about identical decrease of prothrombin level. This indicates that no PIVKA is released to plasma. The functional defect of the hepatocyte does not involve gamma carboxylation as long as vitamin K is provided. In patients with DIC ecarin test showed significantly higher level of thrombin activity than those obtained with Quick's test. It is known that during hypercoagulation stage of DIC prethrombin 1 and 2 are formed by the excess of thrombin. These split products of prothrombin are convertible by ecarin to meizothrombin 1 and 2. A positive ecarin test can be also due to acarboxylated precursors which are released during increased proteosynthesis triggered by consumption coagulopathy.

Topics: Diagnosis, Differential; Dicumarol; Disseminated Intravascular Coagulation; Endopeptidases; Fibrinolytic Agents; Humans; Liver Diseases; Prothrombin

Topics: Anemia, Neonatal; Blood Coagulation Factors; Dicumarol; Erythroblastosis, Fetal; Factor VIII; Female; Fibrinogen; Hemophilia A; Hemophilia B; Hemorrhage; Hepatitis A; Humans; Immunization, Passive; Immunoglobulins; Infant, Newborn; Infusions, Parenteral; Injections, Intravenous; Liver Diseases; Plasma; Pregnancy; Tetanus; Tissue Extracts

Topics: Blood Coagulation Disorders; Blood Transfusion; Dicumarol; Factor VII; Factor X; Factor XI; Hemophilia A; Humans; Liver Diseases; Male; Prothrombin; Vitamin K Deficiency; Vitamin K Deficiency Bleeding

Topics: Animals; Anura; Arteries; Chromatography, Gel; Chromatography, Ion Exchange; Dicumarol; Heart Atria; Hepatic Veins; Humans; Hypertension; Ion Exchange Resins; Iproniazid; Liver Diseases; Methods; Muscle Contraction; Muscle, Smooth; Muscles; Peptides; Pituitary Gland; Spleen

Topics: Alanine Transaminase; Aspartate Aminotransferases; Brain Diseases; Clinical Enzyme Tests; Dicumarol; Ethyl Biscoumacetate; Heart Diseases; Humans; Infectious Mononucleosis; Liver Diseases; Muscular Diseases; Myocardial Infarction; Pancreatitis; Transaminases

Topics: Anticoagulants; Arrhythmias, Cardiac; Blood Cell Count; Cerebrovascular Disorders; Coronary Disease; Diabetes Mellitus; Dicumarol; Heart Failure; Heparin; Humans; Hypertension; Kidney Diseases; Liver Diseases; Myocardial Infarction; Peptic Ulcer; Pulmonary Embolism; Shock; Thromboembolism; Thrombophlebitis; Thrombosis; Varicose Veins; Warfarin

Topics: Biochemical Phenomena; Biochemistry; Blood Coagulation Factors; Blood Coagulation Tests; Dicumarol; Enzyme Precursors; Factor IX; Factor VII; Factor X; Humans; Hypoprothrombinemias; Liver Diseases; Liver Function Tests; Prothrombin; Vitamin K; Vitamin K Deficiency

Topics: Anticoagulants; Blood Coagulation Factors; Dicumarol; Heparin Antagonists; Humans; Liver Diseases; Prothrombin; Vitamin K

Topics: Anticoagulants; Dicumarol; Disease Susceptibility; Hematologic Diseases; Hemophilia A; Hemorrhagic Disorders; Heparin; Humans; Liver Diseases; Purpura, Thrombocytopenic; Purpura, Thrombocytopenic, Idiopathic; Syndrome; Thrombophlebitis

Topics: Dicumarol; Liver; Liver Diseases