Novel mechanisms in chemically induced hepatotoxicity ¹

Abstract

This review focuses on cellular events that modulate hepatotoxicity subsequent to initial liver insult. Cellular events that determine the nature and extent of hepatotoxic injury and the ultimate outcome of that injury are also discussed. The roles of cell types other than hepatocytes, hepatocyte organelle-specific processes, and regeneration in progression or recovery from liver injury are emphasized. Leukocyte activities are key events in two distinct hepatotoxicities. Neutrophil-mediated, periportal inflammation appears to play a primary role in progression of alpha-naphthylisothiocyanate-induced cholangiolitic hepatitis. However, a humorally mediated autoimmune response to protein adducts that occurs after anesthesia is critical in onset of halothane-induced hepatitis. New insights into specific events at the hepatocyte level are also emerging. Although reducing gap junctional communication between hepatocytes can protect against progression of liver injury, down-regulation of the subunit proteins (connexins) can isolate neoplastic cells from growth regulation. Acidic intracellular pH characteristic of hypoxia is protective against both hypoxic and toxicant-induced cell injury. In oxidative injury, a pH-mediated mitochondrial permeability transition causes mitochondrial uncoupling and ATP loss and leads to cell death. The ultimate outcome of hepatotoxic injury depends on the extent of tissue repair. Stimulation of tissue repair after a sublethal dose of CCl4 appears to be the central mechanism in protection against death from a subsequent large dose. Taken together, these examples illustrate the importance of events subsequent to initial liver injury as determinants of extent of liver damage.

Influence of aminoguanidine on parameters of liver injury and regeneration induced in rats by a necrogenic dose of thioacetamide

“…Thioacetamide-induced liver injury is a well established area of considerable pharmacological interest, since reactive oxygen species and free radicals, generated in the microsomal drug oxidation, participate in the mechanisms of cell death (Cascales et al, 1991;Mehendale et al, 1994;Sanz et al, 1998b). In the present study thioacetamide hepatotoxicity was used to investigate the e ect of a single dose of aminoguanidine on the multistep events involved in liver damage and regeneration.…”

Attenuated liver fibrosis and depressed serum albumin levels in carbon tetrachloride-treated IL-6-deficient mice

“…An electron is added to CCl 4 on binding to ferric cytochrome P 450 , resulting in a highly reactive trichloromethyl free radical being generated by the reductive cleavage of the carbon-chloride bond. The generated trichloromethyl free radical causes liver cell necrosis as well as destruction of the extracellular matrix, through lipid peroxidation of membranes [31,33]. In addition to its cytotoxic effects, CCl 4 activates several transcription factors [31], including NF-B [34], a transcription factor complex essentially involved in several inflammatory cytokines, including IL-6 [35].…”

The Nrf2 transcription factor protects from toxin-induced liver injury and fibrosis

“…24 In contrast, liver damage caused by hepatotoxic chemicals induces compensatory hepatic hyperplasia after severe liver necrosis due to direct damage of hepatocytes and subsequent inflammation. 25 To determine if Nrf2 is also protective under these more harmful conditions, we utilized CCl 4 as a model hepatotoxic agent that allowed the evaluation of both necrosis and subsequent inflammation 26 and fibrosis. 17 Furthermore, acute CCl 4 treatment had recently been shown to induce nuclear translocation of Nrf2 and activation of the Nrf2 target gene heme oxygenase-1.…”