COMPARISON OF VARIOUS LAZAROID COMPOUNDS FOR PROTECTION AGAINST ISCHEMIC LIVER-INJURY

Lazaroids are a group of 21-aminosteroids that lack steroid action but have a potent cytoprotective effect by inhibiting iron-dependent Lipi d peroxidation. However, there have been conflicting reports on the ef fectiveness and potency of the various lazaroid compounds. In this stu dy,we compared the effectiveness of three major lazaroids on warm live r ischemia in dogs using a 2-hr hepatic vascular exclusion model. The agents were given to the animals intravenously for 30 min before ische mia. The animals were divided into 5 groups: Control (n=10), no treatm ent; Group F (n=6), U-74006F (10 mg/kg); Group G (n=6), U-74389G (10 m g/kg); Group Al (n=6), U-74500A (10 mg/kg); Group A2 (n=6), U-74500A ( 5 mg/kg). The effect of treatment was evaluated by two-week animal sur vival, hepatic tissue blood flow, liver function tests, blood and tiss ue biochemistry, and histological. analyses. Animal survival in all tr eated groups was significantly improved compared with the control (83- 100% versus 30%). Elevation of liver enzymes after reperfusion was mar kedly attenuated in treated groups, except for an early significant in crease in Group G. Postreperfusion hepatic tissue blood Bow was much h igher in all treated animals (50% of the preischemic level vs. 25% in the control). Lazaroids, particularly U-74500A at 5 mg/kg (Group A2), suppressed adenine nucleotide degradation during ischemia and enhanced the resynthesis of high-energy phosphates after reperfusion. Although structural abnormalities in postreperfusion liver tissues were marked ly ameliorated in all treated groups, Group A2 showed significantly le ss neutrophil infiltration. Liver injury from warm ischemia and reperf usion was attenuated with all lazaroid compounds, of which U-74500A at 5 mg/kg exhibited the most significant protective activity.