Liver damage results

Administration of bromobcnzcnc to rats causes severe liver necrosis. Extensive in vivo and in vitro studies indicate that the liver damage results from the interaction of a chemically reactive metabolite, 4-bromobcnzcnc oxide, with hcpatocytcs. " Extensive covalent binding to hepatic tissue... 

Primary events. As already mentioned many compounds are toxic following metabolism to reactive metabolites. These reactive metabolites may then initiate one or more primary events. For example, paracetamol and bromobenzene-induced liver damage results from metabolic activation, discussed in more detail in Chapter 7. In other cases metabolic activation is not necessary, and the parent compound or a stable metabolite initiates the primary event. For example, cyanide is cytotoxic as a result of inhibition of crucial enzymes and carbon monoxide deprives the cell of oxygen (see Chapter 7 for more details). 

HEALTH SYMPTOMS inhalation (respiratory distress, irritates eyes, skin and respiratory system) skin contact (possible dermatitis, allergic reactions, itching, pigmentation, cancerous changes) ingestion (loss of appetite, cramps, nausea, constipation, diarrhea, liver damage (resulting in jaundice)). 

CHRONIC HEALTH RISKS repeated exposure can lead to an acne-form dermatitis exposure can cause severe liver damage, resulting in such effects as yellow jaundice, dark urine, and fatigue. 

Methimazole can cause liver damage that is typically characterized by cholestasis, but no cases of liver damage resulting in transplantation or death have been described [17 ]. A 60-year-old man with hyperthyroidism developed cholestasis and acute cholecystitis after taking methimazole for 4 days the cholestasis improved rapidly after withdrawal of antithyroid drug therapy [19 ]. 

The toxicity of chloronaphthalenes requires that special attention and caution be used during their manufacture and use acne is the most common result of excessive skin exposure to them and the most frequendy affected areas are the face and neck (16). Liver damage has occurred in workers who have been exposed repeatedly to vapors, particulady to those of penta- and hexachloronaphthalene [1335-87-1] (17,18). Uses for the chlorinated naphthalenes include solvents, gauge and instmment duids, capacitor impregnants, components in electric insulating compounds, and electroplating stop-off compounds. 

Toxicity. Many /V-nitrosamines are toxic to animals and cells in culture (4,6—8,88). /V-Nitrosodimethy1amine [62-75-9] (NDMA) is known to be acutely toxic to the Hver in humans, and exposure can result in death (89). Liver damage, diffuse bleeding, edema, and inflammation are toxic effects observed in humans as a result of acute and subacute exposure to NDMA. These effects closely resemble those observed in animals dosed with NDMA (89,90). 

When administering tacrine, the nurse must monitor the patient for liver damage. This is best accomplished by monitoring alanine aminotransferase (AIT) levels. ALT is an enzyme found predominately in the liver. Disease or injury to the liver causes a release of tiiis enzyme into the bloodstream, resulting in elevated ALT levels, hi patients taking tacrine, ALT levels should be obtained weekly from at least week 4 to week 16 after die initiation of tiierapy. After week 16, transaminase levels are monitored every 3 months. 

A protease-specific model has also been reported in which a replication-defective adenovirus encoding an NS3 protease-SEAP fusion protein is injected into mouse tail veins, resulting in expression of the fusion protein in the liver [82, 83]. Protease activity can be detected both by measuring activity of liberated SEAP or by protease-induced liver damage. Protease activity was found to be reduced by administration of protease inhibitors. This model can be used to show that candidate inhibitors have adequate pharmacokinetic properties in mice to function in the intended target organ, but it is not a true disease model. 

In humans, mild jaundice lasting several days to 4 weeks has been observed after acute occupational exposure to acrylonitrile vapors at high concentrations (Wilson 1944) however, the concentrations of acrylonitrile to which workers were exposed were not reported. The effects were fully reversible. In factory workers exposed to acrylonitrile for 10 years or more, Sakurai et al. (1978) reported an increase in palpable livers of workers. However, the authors considered these results to be inconclusive because the increase was not statistically significant and subjective judgments were involved. Also, blood chemistry evaluations did not indicate liver damage. 

The efficiency of vitamin E in the suppression of free radical-mediated damage induced by iron overload has been studied in animals and humans. Galleano and Puntarulo [46] showed that iron overload increased lipid and protein peroxidation in rat liver. Vitamin E supplementation successfully suppressed these effects and led to an increase in a-tocopherol, ubiquinone-9, and ubiquinone-10 contents in liver. Important results were obtained by Roob et al. [47] who found that vitamin E supplementation attenuated lipid peroxidation (measured as plasma MDA and plasma lipid peroxides) in patients on hemodialysis after receiving iron hydroxide sucrose complex intravenously during hemodialysis session. These findings support the proposal that iron overload enhances free radical-mediated damage in humans. 

Overproduction of free radicals by erythrocytes and leukocytes and iron overload result in a sharp increase in free radical damage in T1 patients. Thus, Livrea et al. [385] found a twofold increase in the levels of conjugated dienes, MDA, and protein carbonyls with respect to control in serum from 42 (3-thalassemic patients. Simultaneously, there was a decrease in the content of antioxidant vitamins C (44%) and E (42%). It was suggested that the iron-induced liver damage in thalassemia may play a major role in the depletion of antioxidant vitamins. Plasma thiobarbituric acid-reactive substances (TBARS) and conjugated dienes were elevated in (3-thalassemic children compared to controls together with compensatory increase in SOD activity [386]. The development of lipid peroxidation in thalassemic erythrocytes probably depends on a decrease in reduced glutathione level and decreased catalase activity [387]. 

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