Kupffer Cell Stimulation with Corynebacterium parvum Reduces Some Cytochrome P450-Dependent Activities and Diminishes Acetaminophen and Carbon Tetrachloride-Induced Liver Injury in the Rat

Abstract

Chemical activation of Kupffer cells in vivo by vitamin A or latex beads is associated with a worsening of hepatic injury induced by the P450-dependent hepatotoxins acetaminophen (ACET) and carbon tetrachloride (CCl4) and by the P450-independent toxin galactosamine (GLN). Immunostimulants such as Corynebacterium parvum (CP) also activate Kupffer cells, but do so while prompting release of soluble mediators which depress microsomal oxidative activities in cultured hepatocytes. Therefore, we sought to characterize the effects of CP on hepatic injury in vivo due to ACET and CCl4 while employing GLN as a control. Hepatic microsomal oxidative activity and glutathione (GSH) disposition were examined since each influences susceptibility to injury from ACET or CCl4. Rats were given CP 28 mg/kg iv 5 days before challenge with hepatotoxicant. Hepatic injury was assessed 24 hr after hepatotoxicant administration by measurement of serum alanine aminotransferase (ALT) activity and review of histological sections. Livers from parallel groups of rats were used to prepare microsomal and cytosolic fractions, to measure tissue GSH, or for perfusion to assess GSH efflux. Significant reductions in injury due to ACET or CCl4 were observed while injury due to GLN was potentiated. Serum ALT levels after ACET were 3000 ± 620 in controls vs 170 ± 45 IU/liter in the CP-treated group and ALT levels after CCl4 were 3100 ± 500 in controls vs 1700 ± 450 IU/liter in the CP-treated group. In contrast, serum ALT levels after GLN were 920 ± 230 in controls vs 1700 ± 370 in the CP-treated group. Patterns of hepatic injury observed on histological sections were those characteristic for each toxin and the severity of injury correlated well with alterations in serum ALT levels for each agent. Hepatic microsomal fractions from rats pretreated with CP showed significantly diminished total cytochrome P450 content as well as reduced activity for two P450IIE1 substrates, p-nitrophenol and 7-ethoxycoumarin. While sinusoidal efflux of GSH increased by 40% in rats pretreated with CP and cytosolic glutathione-S-transferase activity fell slightly, tissue GSH levels were unaffected. These data demonstrate that CP decreases microsomal cytochrome P450 content, reduces biotransformation of two P450IIE1 substrates, and diminishes ACET- and CCl4-induced hepatic injury. In contrast, hepatic injury due to the P450-independent toxin GLN was enhanced. Thus, chemical and immune stimulation of Kupffer cells may result in divergent effects on susceptibility to injury from individual hepatotoxins.