Acute Hepatotoxicity of Adriamycin-Oxidized Dextran (ADM-OXD) in Rat

Acute hepatotoxicity of adriamycin-oxidized dextran (ADM-OXD), a newly developed antineoplastic macromolecule, was compared with that of adriamycin (ADM). Biochemical parameters of hepatic function and morphological changes were monitored up to day 3 after intravenous administration of ADM-OXD or ADM to male Wistar rats at a single dose of 45 mg/kg, measured by ADM content. From day 1 after ADM-OXD administration, lipid peroxide (LPO) level in the liver tended to increase and serum transaminase activity showed pronounced elevation from day 2. Morphologically, hyaline degeneration and single cell necrosis of hepatocyte were noted from day 0 (8 hours) to day 1 and resulted in diffuse centrilobular degeneration and necrosis on day 2. ADM administration did not induce hepatotoxicity, though it did induce acute cardiotoxicity. ADM-OXD-induced acute hepatotoxicity was amplified by intermittent treatment with glutathione depleting agent after drug administration and abated by antioxidative agent. These results indicate that oxidative stress is involved in the onset of hepatotoxicity induced by ADM-OXD. Quantitative determination by HPLC after ADM administration revealed immediate excretion of ADM from the liver. After ADM-OXD administration, on the other hand, ADM levels increased gradually and peaked on days 1 and 2. Hepatotoxicity specific to ADM-OXD is essentially attributable to this long-term retention of ADM. Furthermore, observation by fluorescent microscope revealed that ADM was distributed not only to hepatocytes but also to sinusoidal lining cells after ADM-OXD administration.