Reactive oxygen species in the progression of CCl4-induced liver injury.
Pretreatment of rats with large doses of vitamin A (retinol) dramatically increased the hepatotoxicity of carbon tetrachloride (CCl4). Experiments were performed to elucidate the mechanism of this potentiation. Hypervitaminosis A was produced by oral administration of retinol, 250,000 IU/kg for seven days. CCl4 was then administered at a dose of 0.15 ml/kg, ip. This large dose of vitamin A did not enhance the biotransformation of CCl4, but did produce a 4-fold increase in CCl4-induced lipid peroxidation, as assessed by ethane exhalation. Because vitamin A has been shown to activate macrophages, it was hypothesized that this increased lipid peroxidation and liver injury resulted from the release of reactive oxygen species from activated Kupffer cells. By using a chemiluminescence assay, an enhanced release of free radicals was detected in Kupffer cells isolated from vitamin A pretreated rats. In addition, Kupffer cells from vitamin A pretreated rats displayed enhanced phagocytic activity in vitro, towards sheep red blood cells. In vivo, vitamin A pretreated rats cleared carbon particles from the blood 2-3 times faster than non-pretreated rats. In vivo administration of superoxide dismutase (SOD) 2 hr after CCl4 exposure did not influence CCl4 toxicity in control rats but did block the enhanced ethane exhalation and also the potentiation of CCl4 liver injury in vitamin A treated rats. Administration of methyl palmitate, an inhibitor of Kupffer cell function, did not inhibit CCl4 toxicity in control rats, but did effectively block enhanced ethane exhalation and potentiation of CCl4 injury in vitamin A treated rats. We conclude that potentiation of CCl4 hepatotoxicity by hypervitaminosis A is mediated in part by reactive oxygen species released from activated Kupffer cells.
Sipes
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Department of Pharmacology, College of Pharmacy, University of Arizona, Tucson 85721.
el Sisi
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Sim
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Mobley
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Earnest
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D000818:Animals; D001711:Biotransformation / Q000187:drug effects; D002251:Carbon Tetrachloride / Q000493:pharmacokinetics / Q000633:toxicity*; D004357:Drug Synergism; D005609:Free Radicals; D007728:Kupffer Cells / Q000187:drug effects; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D010100:Oxygen / Q000378:metabolism*; D010587:Phagocytosis / Q000187:drug effects; D051381:Rats; D011919:Rats, Inbred Strains; D014801:Vitamin A / Q000494:pharmacology
D005609:Free Radicals; D014801:Vitamin A; D002251:Carbon Tetrachloride; D010100:Oxygen