Page 388 - The Toxicology of Fishes

368 The Toxicology of Fishes

Cell Interaction
A mechanistic understanding of the mode of action of various xenobiotics is possible only with knowl-
edge of the cell types involved in the activation and deactivation of the compound and those that become
targets for toxicants. Current mammalian liver toxicity studies demonstrate signaling between individual
cell types that often determines the site and extent of toxicity (Treinen-Moslen, 2001). Hepatotoxicants
such as acetaminophen or carbon tetrachloride, for example, can lead to an increased number and
activation of macrophages, including the resident macrophages (i.e., Kupffer cells) in the rodent liver
(Laskin and Gardner, 1998). Also, the sinusoidal endothelial cells and stellate cells can increase in
number and become activated following exposure of rodents to hepatotoxicants. The activation of the
sinusoidal cells may occur through factors released by damaged hepatocytes (Treinen-Moslen, 2001).
The activated cells release mediators such as reactive oxygen intermediates, reactive nitrogen interme-
diates, cytokines, bioactive lipids, and hydrolytic enzymes that then are responsible for sequelae reactions
(Dong et al., 1998; Ganey et al., 2001; Junge et al., 2001; Morio et al., 2001). In the stellate cells,
collagen production is stimulated (Treinen-Moslen, 2001). The mediators released by the nonhepatocyte
cells can be directly cytotoxic, but they are also able to modify hepatocyte signaling pathways or
xenobiotic metabolism (Cain and Freathy, 2001; Renton, 2000). Perhaps the best evidence for a role of
macrophages in the pathogenesis of liver injury comes from studies where the experimental depression
of macrophage function diminished hepatotoxicity (Junge et al., 2001; Laskin and Gardner 1998). Few
studies have addressed the possible role of nonhepatocyte cells, inflammatory macrophages, and mac-
rophage-derived factors in liver damage in fish.
From studies on the acute phase response of fish, evidence has been obtained that salmon hepatocytes
possess cytokine receptors and that bacterial lipopolysaccharide (LPS) induces serum amyloid A tran-
scription in the hepatocytes (Jorgensen et al., 2000); however, whether this response was a direct effect
of LPS on the hepatocytes or mediated by other liver cell types was not determined. Pollutant-induced
activation of catfish (Heteropneustes fossilis) macrophages was associated with a concomitant increase
in peroxidative tissue damage (Fatima et al., 2000). The liver, however, showed the weakest response
among the three target organs studied (gills, liver, kidney). In mammalian liver, cytokines suppress
hepatic cytochrome P450 enzymes (Renton, 2000), and, as reported by Marionnet et al. (1998), they
also suppress cytochrome P450 activities in fish liver. Furthermore, while cell types of livers of fishes
are for the most part the same as those found in the livers of their mammalian counterparts, there are
some differences. Exocrine pancreatic tissue is found in the connective tissue of the hepatic portal vein
(variable with species) and some of its branches within the livers of certain species (e.g., carp)
(Figueiredo-Fernandes et al., 2007; Vogt and Segner, 1997). This is not the general case in mammalian
species. The Kupffer cell, a resident macrophage in hepatic sinusoids of mammals, is not found in most
fish species (see Table 7.1). For those species in which the cells are present, their functions have been
only partially determined (Hampton et al., 1987). Although the other cell types (see descriptions above)
are found, their role in hepatotoxicity in fish has not been well characterized, and we have little or no
information regarding signaling between various resident cells. This area requires future attention. The
role of these cells in immune reactions and in initiating and mediating liver toxicity is not known. We
do not know why certain hepatoxicants preferentially damage one cell type and if there exists preferential
uptake or metabolism of certain toxicants by specific liver cell types. How the cells of the hepatic
sinusoids and those involved in immune function influence liver pathogenesis is an area that so far has
not been addressed in fishes.

Metabolism as Factor in Liver Toxicity
Xenobiotic metabolism and activation is an important factor in liver toxicity. Toxicity of a chemical may
be due to the parent compound or to a metabolite generated by metabolic conversion of the former to
reactive electrophiles that combine covalently with critical cellular macromolecules such as proteins,
DNA, or RNA. The liver is the major site of biotransformation in fish and performs both phase I and
phase II reactions of xenobiotic metabolism. Liver xenobiotic metabolism has important consequences