ABSTRACT
Considerable evidence has accumulated over the past several years demonstrating that
hepatotoxicity induced by a diverse group of drugs and chemicals is due not only to a direct
effect of these compounds on the liver, but also indirectly to the actions of inflammatory
mediators released by nonparenchymal cells, in particular hepatic sinusoidal cells, including
macrophages, endothelial cells, and stellate cells, as well as infiltrating leukocytes. Following
exposure of experimental animals to hepatotoxicants, these cells become “activated.” This
involves alterations in their functional and biochemical properties leading to the release of an
array of proinflammatory and cytotoxic mediators that have the capacity to promote liver
damage. These findings, together with the observation that hepatotoxicity can be modified by
agents that modulate inflammatory cell and mediator activity, provide direct evidence that
these cells contribute to tissue injury. The mediators involved in the cytotoxic process include
reactive oxygen and reactive nitrogen intermediates, proinflammatory cytokines, proteolytic
enzymes, eicosanoids, and/or bioactive lipids released at sites of injury. Whereas some of these
mediators are directly cytotoxic (e.g., hydrogen peroxide, nitric oxide, peroxynitrite), others
degrade the extracellular matrix (e.g., collagenase, elastase) and/or promote inflammatory cell
adhesion and infiltration, and nonparenchymal cell proliferation and activation (e.g., inter-
leukin-1 (IL-1), interleukin-6 (IL-6), tumor necrosis factor-a (TNFa), transforming growth
factor-b, (TGFb), platelet-activating factor (PAF), chemokines, and colony-stimulating
factors). There is also evidence that some of the mediators produced by activated nonpar-
enchymal cells and inflammatory macrophages canmodify hepatocyte protein and nucleic acid
biosynthesis, as well as cytochrome P450-mediated xenobiotic metabolism, which may also
contribute to hepatotoxicity. In this chapter, experimental evidence implicating nonparench-
ymal cells and inflammatory macrophages and mediators produced by these cells in
hepatotoxicity is reviewed.
