Vol. 284, Issue 1, 406-412, 1998

The 21-Aminosteroid 16-Desmethyl Tirilazad Mesylate Prevents Necroinflammatory Changes in Experimental Alcoholic Liver Disease

S. M. Hossein Sadrzadeh and Amin A. Nanji

Department of Pathology (S.M.H.S.), University Medical Center, The University of Arizona, Tucson, Arizona, and the Department of Pathology (A.A.N.), Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts

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- (TNF-) 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- 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- and COX-2. Membrane stabilization may also, by reducing lipid peroxidation, play an additional role in preventing liver injury.