Abstract
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-α (TNF-α) 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-α 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-α and COX-2. Membrane stabilization may also, by reducing lipid peroxidation, play an additional role in preventing liver injury.
Footnotes
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Send reprint requests to: Dr. S. M. Hossein Sadrzadeh, Department of Pathology, University Medical Center, The University of Arizona, P.O. Box 245043, Tucson, AZ 85724-5043.
- Abbreviations:
- CaM
- calmodulin-stimulated Ca++pump ATPase
- COX
- cyclooxygenase
- FD
- fish oil and dextrose
- FE
- fish oil and ethanol
- FE-LAZ
- fish oil plus ethanol plus the 21-aminosteroid U74389 (lazaroid)
- FD-LAZ
- fish oil plus dextrose plus the 21-aminosteroid U74389 (lazaroid)
- NF-κB
- nuclear factor-κB
- TBARS
- thiobarbituric acid reactive substances
- TNF
- tumor necrosis factor
- RT
- reverse transcription
- PCR
- polymerase chain reaction
- Received March 19, 1997.
- Accepted August 20, 1997.
- The American Society for Pharmacology and Experimental Therapeutics
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