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The liver is especially susceptible to the toxic effects of methionine due to its role in sulfur amino acid metabolism. Therefore, the excessive amounts of this amino acid may induce liver damage. To test the mechanisms of methionine-related hepatotoxicity, liver thiobarbituric acid reactive substances (TBARS), and activities of superoxide dismutase, catalase and selenium-dependent glutathione peroxidase were measured in rabbits fed a methionine-enriched diet for 6 or 9 mo. Morphological studies of livers were also made. Feeding rabbits the methionine-enriched diet for 9 mo resulted in a significant increase in liver TBARS levels and antioxidant enzyme activities. Moreover, an inflammatory infiltration of portal triads in the treated rabbits were observed. These results indicate that methionine may induce hepatitis by increasing free radical processes.

Elastin-derived peptides, kappa-elastin, prepared by chemical degradation of insoluble elastin from bovine ligamentum nuchae, were shown to increase the elastase-like activity in the culture medium and cell fractions in fibroblasts. Preincubation of cells with nifedipine (calcium channel blocker) and trifluoperazine (calmodulin antagonist) induced a decrease in the activities of the enzyme under study. These data suggest the possibility of pharmacological modulation of the biological effects induced by elastin-derived peptides.

1. Four groups of rats were injected with four different anti-inflammatory drugs (indomethacin, phenylbutazone, acetylsalicylic acid and hydrocortisone) and the activities of superoxide dismutase, catalase and glutathione peroxidase were studied in the liver and kidney. 2. The drugs treatment resulted in decreased activity of the enzymes in both organs compared to the control animals. 3. In vivo tissue peroxidation was also effected by the drugs used. 4. Our results indicate that the changes of oxygen free-radical metabolism contribute to the action of these drugs in vivo.

The retinol effect on symptoms of late toxicity of hydralazine in rats of Wistar strain during induction of the collagenosis-like syndrome has been studied. Studies have been performed during 360 days, and examination were done in three months lasting intervals. Animals were divided into 3 groups: the first was treated with hydralazine, the second with hydralazine plus retinol, and the third corresponded to the control group. It has been stated that the long-term administration of hydralazine caused the lowering of the retinol level in the serum and liver progressing according to the time of the drug use. The mean lowering of the retinol concentration for animals of the first group was 20.7% in the serum and 24.7% in the liver. Analogous results in the second group were 12.1% and 14.7%, respectively. Simultaneously activity of superoxide dismutase measured in the kidney and heart muscle homogenates was significantly lowered in animals receiving hydralazine solely. Retinol administered together with hydralazine caused an increase in the enzyme activity (about 30%) when compare with animals treated only with hydralazine. The lowering of the retinol level and of dismutase activity caused beneficial conditions for increased lipid peroxidation measured by an increase in the malonic aldehyde concentration. The concentration of malonic dialdehyde in kidneys of rats treated solely with hydralazine increased about twofold, and in the heart muscle about 3.5-fold. The supplementation of the diet with retinol in rats treated solely with hydralazine partially limited effects of enhanced free radical activity reflected in increased lipid peroxidation.

The metabolism of hydralazine and its pyruvic acid hydrazone was studied in a medium containing isolated adult rat hepatocytes. Hydralazine undergoes conversion to 3-methyltriazolophthalazine, while hydralazine pyruvic acid hydrazone is not metabolized in rat hepatocytes.

A drug-induced collagen-like syndrome was produced in rats by hydralazine administration for 8, 9 and 10 months. The hyaluronic acid content and the hyaluronidase activity in liver and spleen were studied. A decrease in the hyaluronic acid amount was accompanied by an enhanced activity of hyaluronidase in both tissues. The results provide evidence for metabolic disturbances of glycosaminoglycans in the connective tissue in the collagen disease-like syndrome.

Collagen content was measured in the skin, liver, lungs, kidneys and heart muscle of rats irradiated with a single dose of gamma rays (500 R). A decrease of total collagen content was found in the skin and was produced by a decrease of neural salt-soluble and acid-soluble collagen. A slight increase of insoluble collagen was observed in the skin, liver and lungs.

Influence of the administration of thyroid extract and of methylthiouracil on the collagen content in the liver and on hydroxyproline level in serum in rats with or without carbon tetrachloride-induced fibrosis of the liver was investigated. A decrease of collagen content in the liver was found in hyperthyroid rats and an increase of the liver collagen content was observed in hypothyreosis. Similar results were found in animals with fibrosis of the liver.

Hepatic fibrosis was induced in rats by poisoning them with carbon tetrachloride. The influence of anti-inflammatory steroids (hydrocortisone, prednisone, dexamathasone) upon elastin content in liver was investigated in healthy and CCl4 intoxicated rats. An increase of liver elastin content was observed in animals with CCl4-induced hepatic fibrosis Opposite results were obtained in normal rats after treating them with glucocorticosteroids. A decrease of elastin content after steroid treatment was also found in rats with injured liver, as compared to animals receiving CCl4 only. Presumable mechanisms of the results are discussed.