Inhibition of carbon tetrachloride-induced liver injury by liposomes containing vitamin E.
We tested a variety of antioxidants as possible therapeutic agents in an acute CCl4 mouse model of hepatotoxicity. Liver damage, gauged by the amount of serum aminotransferase released into the blood, morphological changes, lethal dose response, and presence of thiobarbituric acid-reactive substances (TBARS), were significantly inhibited in a dose-dependent manner by liposomes containing vitamin E (LVE) or by Rocavit E, a water-soluble emulsion of alpha-tocopherol. Serum aminotransferase levels in LVE- or Rocavit E-treated animals were always > 10-fold lower than levels in corresponding CCl4 controls. Other liposome-associated antioxidants, butylated hydroxytoluene, vitamin E succinate, catalase, desferoxamine, superoxide dismutase, and ascorbic acid 6-palmitate, were also able to elicit a decrease in damage; however, they were substantially less effective. Intravenous therapy with LVE decreased mortality by nearly 90% when a lethal dose of CCl4 was given. When the biodistribution of the liposomes was examined, it was determined that the vast majority were localized in the Kupffer cell population. This approach of delivering nontoxic therapeutic agents selectively to the liver offers a variety of clinical applications in humans.
Yao
T
T
Department of Medicine, Jefferson Medical College, Thomas Jefferson University, Philadelphia 19107.
Degli Esposti
S
S
Huang
L
L
Arnon
R
R
Spangenberger
A
A
Zern
M A
MA
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D002232:Carbocyanines; D002251:Carbon Tetrachloride / Q000009:adverse effects*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005456:Fluorescent Dyes; D007274:Injections, Intraperitoneal; D008054:Lipid Peroxides / Q000037:antagonists & inhibitors; D008081:Liposomes; D008099:Liver / Q000187:drug effects* / Q000473:pathology; D051379:Mice; D008815:Mice, Inbred Strains; D009336:Necrosis; D016019:Survival Analysis; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism; D014018:Tissue Distribution; D014810:Vitamin E / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology
D000975:Antioxidants; D002232:Carbocyanines; D005456:Fluorescent Dyes; D008054:Lipid Peroxides; D008081:Liposomes; C089533:Rocavit E; D017392:Thiobarbituric Acid Reactive Substances; D014810:Vitamin E; C024286:3,3'-dioctadecylindocarbocyanine; D002251:Carbon Tetrachloride