The 21-aminosteroid 16-desmethyl tirilazad mesylate prevents necroinflammatory changes in experimental alcoholic liver disease

We investigated the potential of 16-desmethyl tirilazad mesylate, a member of 21-aminosteroids, to ameliorate alcohol-induced liver injury. Four groups (five rats/group) of male Wistar rats were studied. One group of rats was fed fish oil and ethanol (FE) for 4 weeks, and a second group received isocaloric amounts of dextrose instead of ethanol (FD). The third (FE-LAZ) and fourth (FD-LAZ) groups received the addition of 10 mg/kg/day of 16-desmethyl tirilazad mesylate (U74389) daily via intragastric tube. Liver samples were analyzed for histopathology, nonheme iron, lipid peroxidation and levels of mRNA for tumor necrosis factor-alpha (TNF-alpha) and cyclooxygenase-2 (COX-2). Concentrations of endotoxin and 8-isoprostane were measured in plasma. Membrane ATPases were measured in isolated membrane red cells. FE rats developed fatty liver, necrosis and inflammation. Treatment with the 21-aminosteroid resulted in prevention of necroinflammatory changes, but the degree of fatty liver was unchanged. The absence of necroinflammatory changes in the FE-LAZ group was accompanied by a decrease in levels of nonheme iron, lipid peroxidation, TNF-alpha mRNA and COX-2 mRNA. Ethanol administration decreased membrane Ca(++)-ATPase and calmodulin-stimulated Ca(++)-ATPase, and the decrease was reversed by 21-aminosteroid treatment. The data indicate that the improvement in the degree of necrosis and inflammation in the rats treated with the 21-aminosteroid may be explained, at least in part, by reduced levels of proinflammatory stimuli such as lipid peroxidation, TNF-alpha and COX-2. Membrane stabilization may also, by reducing lipid peroxidation, play an additional role in preventing liver injury.