Aerobic organisms by definition require oxygen, and the importance of iron in aerobic respiration has long been recognized, but despite their beneficial roles, these elements can pose a real threat to the organism. During oxygen reduction, reactive species such as O2-. and H2O2 are formed readily. Iron can combine with these species, or with molecular oxygen itself, to generate free radicals which will attack the polyunsaturated fatty acids of membrane lipids. This oxidative deterioration of membrane lipids is known as lipid peroxidation. To protect itself against this form of attack, the organism possesses several types of defense mechanisms. Under normal conditions, these defenses appear to offer adequate protection for cell membranes, but the possibility exists that certain foreign compounds may interfere with or even overwhelm these defenses, and herein could lie a general mechanism of toxicity. This possible cause of toxicity is discussed in relation to other suggested causes.

Lipid peroxidation and mechanisms of toxicity.

Propylthiouracil has been shown experimentally to protect against alcohol-induced hepatocellular necrosis in hypoxic conditions. An earlier, short-term study of patients with alcoholism and liver disease indicated clinical improvement with propylthiouracil, but the effect on mortality could not be assessed. In the present study, we investigated the effect of propylthiouracil on mortality in patients with alcoholic liver disease in a long-term, double-blind, randomized clinical trial involving 310 compliant patients who received propylthiouracil (n = 157) or placebo (n = 153) for a maximum of two years. There were no differences between the two groups in demographic and clinical characteristics and biopsy-confirmed diagnoses at randomization, or in daily urinary alcohol levels during the study. The cumulative dropout rate over two years was not significantly different (propylthiouracil group, 0.68; placebo group, 0.60). The group receiving propylthiouracil (300 mg per day) had a cumulative mortality rate half that in the group receiving placebo (0.13 vs. 0.25 [P less than 0.05] in the total sample, and 0.25 vs. 0.55 [P less than 0.03] in a subgroup of severely ill patients [propylthiouracil group, n = 56; placebo group, n = 41]). Proportional-hazards stepwise regression analyses indicated that only propylthiouracil treatment, prothrombin time, hemoglobin levels, and mean daily urinary alcohol levels significantly affected mortality. The hazards ratio for the complete group indicated that mortality in the propylthiouracil group was 0.38 (95 percent confidence interval, 0.20 to 0.83) that of the placebo group. Protection by propylthiouracil was not observed in patients with high morning urinary alcohol levels. No clinically important side effects of propylthiouracil were observed at the dose used. We conclude that the administration of propylthiouracil can reduce mortality due to alcoholic liver disease.

Long-term treatment of alcoholic liver disease with propylthiouracil.

https://www.gastrojournal.org/article/S0016-5085(83)80238-8/pdf

prevention of Acetaminophen and Cocaine Hepatotoxicity in Mice by Cimetidine Treatment

Drug metabolism in extrahepatic diseases

Background— Propylthiouracil (PTU) is used to treat hyperthyroid patients by its hypothyroid effect. PTU also is found to have potent antioxidant and immunosuppressive effects. These findings suggest that PTU may play a role in the prevention of atherosclerosis. Methods and Results— This study evaluates the effect of PTU on atherosclerotic change in rabbits fed a high-cholesterol diet. The pronounced atherosclerotic lesions in the aortas of rabbits fed a 2% cholesterol diet for 12 weeks were significantly attenuated by the concurrent addition of 0.1% PTU to the drinking water. However, exogenous supplementation of thyroid hormone in hypothyroid PTU-treated rabbits did not abrogate the protective effect of PTU on atherogenesis. Immunohistochemical analysis showed that PTU administration apparently reduced the intimal smooth muscle cell/macrophage ratio in the atherosclerotic plaques of rabbits fed a 2% cholesterol diet. In vitro, the addition of PTU to the medium of cultured rat vascular smooth muscle cell...

Protective Effect of Propylthiouracil Independent of Its Hypothyroid Effect on Atherogenesis in Cholesterol-Fed Rabbits PTEN Induction and Inhibition of Vascular Smooth Muscle Cell Proliferation and Migration

D Mahany

Papers

Protective effect of propylthiouracil independent of its hypothyroid effect on acetaminophen toxicity in the rat.