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OtherTOXICOLOGY

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

S. M. Hossein Sadrzadeh and Amin A. Nanji
Journal of Pharmacology and Experimental Therapeutics January 1998, 284 (1) 406-412;
S. M. Hossein Sadrzadeh
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Amin A. Nanji
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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

  • 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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Journal of Pharmacology and Experimental Therapeutics
Vol. 284, Issue 1
1 Jan 1998
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OtherTOXICOLOGY

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

S. M. Hossein Sadrzadeh and Amin A. Nanji
Journal of Pharmacology and Experimental Therapeutics January 1, 1998, 284 (1) 406-412;

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OtherTOXICOLOGY

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

S. M. Hossein Sadrzadeh and Amin A. Nanji
Journal of Pharmacology and Experimental Therapeutics January 1, 1998, 284 (1) 406-412;
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