Abstract
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.
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References
Al-Tuwaijri, A., Akdamar, K. and DiLuzio, R. (1981). Modification of galactosamineinduced liver injury in rats by reticuloendothelial stimulation or depression. Hepatology 1 (2), 107–113.
Bollag, W. (1983). Vitamin A and retinoids: From nutrition to pharmacotherapy in dermatology and oncology. Lancet 1 (8329), 860–863.
Davis, F., Pyatak, P. and Abuchowshi, A. (1980). Preparation of PEG-SOD adduct and an examination of its blood circulating life and anti-inflammatory activity. Res. Comm. Chem. Pathol. Pharmacol. 29 (1), 113–127.
Farris, W.A. and Erdman, J.W. (1982). Protracted hypervitaminosis A following longterm, low-level intake. JAMA 247, 1317–1318.
Fujiwara, K., Ogata, I. and Mochida, S. (1989). In situ evaluation of stimulatory state of hepatic macrophage based on ability to produce superoxide in rats. In, Cells of the Hepatic Sinusoid, Vol. 2 (E. Wisse, D.L. Knook and K. Decker, eds.), pp. 204–205, Kupffer Cell Foundation, The Netherlands.
Howard, W.B. and Willhite, C. (1986). Toxicity of retinoids in humans and animals. J. Toxicol.–Toxin Reviews 5, 55–94.
Ishak, K.G. (1987). New development in diagnostic liver pathology. In, Pathogenesis of Liver Disease ( E. Farber, M.J. Phillips and N. Kaufman, eds.), pp. 223–373, Williams and Wilkins, Baltimore.
Knook, D. and Sleyster, C. (1976). Separation of Kupffer and endothelial cells of rat liver by centrifugal elutriation. Exp. Cell. Res. 99, 445–449.
Krause, R.F. (1965). Liver lipids in a case of hypervitaminosis A. Am. J. Clin. Nutr. 16, 455–457.
Lee, P., Walker, E.R., Miles, P.R. and Castranova, V. (1987). Differential generation of chemiluminescence from various cellular fractions obtained by dog lung lavage. In, Cellular Chemiluminescence, Vol. III. ( K. Van Dyke and V. Castranova, eds.), pp. 53–60, Boca Raton, Florida.
Leo, M.A. and Lieber, C.S. (1983). Hepatic fibrosis after long-term administration of ethanol and moderate vitamin A supplementation in the rat. Hepatology 3, 1–11.
Matuso, S., Nakagawara, A., Ikeda, K., Mitsuyama, M. and Nomoto, K. (1985). Enhanced release of reactive oxygen intermediates by immunologically activated Kupffer cells. Clin. Exp. Immunol. 59, 203–209.
Newton, D. and Sporn, M. (1979). Chemoprevention of cancer with retinoids. Fed. Proc. 58, 2528–2534.
Rubin, E., Florman, A.L., Degnan, T. and Diaz, J. (1970). Hepatic injury in chronic hypervitaminosis A. Amer. J. Dis. Child. 119, 132–138.
Russell, R.M., Boyer, J.L., Bagheri, S.A. and Hruban, Z. (1974). Hepatic injury from chronic hypervitaminosis A resulting in portal hypertension and ascites. N. Eng. J. Med. 291, 435–440.
Sipes, I.G. and Gandolfi, A.J. (1982). Bioactivation of aliphatic organohalogens: Formation, detection and relevance. In, Toxicology of the Liver ( G. Plaa and W. Hewitt, eds.) pp. 181–212, Raven Press, New York.
Triarhou, L. and Cerro, M. (1985). Colloidal carbon as a multilevel marker for experimental lesions. Experientia 41, 620–621.
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© 1991 Plenum Press, New York
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Sipes, I.G., El Sisi, A.E., Sim, W.W., Mobley, S.A., Earnest, D.L. (1991). Reactive Oxygen Species in the Progression of CCl4-Induced Liver Injury. In: Witmer, C.M., Snyder, R.R., Jollow, D.J., Kalf, G.F., Kocsis, J.J., Sipes, I.G. (eds) Biological Reactive Intermediates IV. Advances in Experimental Medicine and Biology, vol 283. Springer, Boston, MA. https://doi.org/10.1007/978-1-4684-5877-0_65
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DOI: https://doi.org/10.1007/978-1-4684-5877-0_65
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