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 lipid peroxidation. However, there have been conflicting reports on the effectiveness and potency of the various lazaroid compounds. In this study, we compared the effectiveness of three major lazaroids on warm liver ischemia in dogs using a 2-hr hepatic vascular exclusion model. The agents were given to the animals intravenously for 30 min before ischemia. The animals were divided into 5 groups: Control (n=10), no treatment; Group F (n=6), U-74006F (10 mg/kg); Group G (n=6), U-74389G (10 mg/kg); Group A1 (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 survival, hepatic tissue blood flow, liver function tests, blood and tissue biochemistry, and histological analyses. Animal survival in all treated groups was significantly improved compared with the control (83-100% versus 30%). Elevation of liver enzymes after reperfusion was markedly attenuated in treated groups, except for an early significant increase in Group G. Postreperfusion hepatic tissue blood flow was much higher 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 markedly ameliorated in all treated groups, Group A2 showed significantly less neutrophil infiltration. Liver injury from warm ischemia and reperfusion was attenuated with all lazaroid compounds, of which U-74500A at 5 mg/kg exhibited the most significant protective activity.
Ishizaki
N
N
The Pittsburgh Transplantation Institute, University of Pittsburgh, Pennsylvania 15213, USA.
Zhu
Y
Y
Zhang
S
S
Nemoto
A
A
Kobayashi
Y
Y
Subbotin
V
V
Starzl
T E
TE
Todo
S
S
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D004285:Dogs; D005260:Female; D007511:Ischemia / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D007770:L-Lactate Dehydrogenase / Q000097:blood; D015227:Lipid Peroxidation / Q000187:drug effects; D008099:Liver / Q000098:blood supply* / Q000187:drug effects / Q000473:pathology; D008111:Liver Function Tests; D008315:Malondialdehyde / Q000032:analysis; D009389:Neovascularization, Pathologic; D011281:Pregnatrienes / Q000494:pharmacology*; D015427:Reperfusion Injury / Q000517:prevention & control*
D000975:Antioxidants; D011281:Pregnatrienes; C074965:U 74389F; D008315:Malondialdehyde; D007770:L-Lactate Dehydrogenase; C053356:U 74500A; C053355:tirilazad