Page 369 - The Toxicology of Fishes

Liver Toxicity 349

The important metabolic role of the liver is related to its unique location within the systemic circulation.
This location is also responsible for the importance of the liver in the uptake, storage, metabolism,
redistribution, and excretion of environmental toxicants and makes it at the same time a target of toxic
substances. The livers of fishes can store large amounts of either glycogen or lipid. The type of storage
product may change with species. Some species, such as salmonids, preferably store glycogen in the
hepatocytes; others, such as cod, deposit large amounts of lipids, and cyprinids can shift between the
deposition of glycogen or lipid (Bohm et al., 1994; Fujita 1985; Welsch and Storch, 1973). Also,
physiological factors such as sex (Braunbeck, 1998; Peute et al., 1978) or environmental factors such
as nutrition or temperature can strongly change the quantity and type (glycogen/lipid) of hepatic energy
stores (see, for example, Braunbeck et al., 1987; Berlin and Dean, 1967; Gas and Serfaty, 1972; Segner
and Braunbeck, 1988, 1990a; Segner and Moller, 1984; Segner and Witt, 1990). Such changes are
indicative of an in-depth reorientation of hepatic metabolism in response to endogenous or exogenous
change, and the changing metabolic state can directly or indirectly influence the toxicant sensitivity of
the fish (Braunbeck and Segner, 1992; Braunbeck et al., 1989; Koehler 2004).

Liver Metabolism

Aspects of liver intermediary metabolism, liver xenobiotic metabolism, and experimental in vitro hepatic
systems have been covered in detail by other reviews and in other chapters of this book. Here, we
summarize a few issues that are important for our coverage in this chapter. We refer interested readers to
the following relevant reviews: For in vitro metabolism, see Mommsen et al. (1994), Pesonen and
Andersson (1997), Denizeau (1998), Monod et al. (1998), and Segner (1998). For information on aspects
of in vivo liver xenobiotic metabolism, see Andersson and Forlin (1992), Stegeman et al. (2004), and
Schlenk et al. (2006). For intermediary metabolism and aspects of liver metabolism, see Cowey and Walton
(1982), Moon and Foster (1995), Navarro and Gutierrez (1995), Hemre et al. (2002), and Moon (2004).
Research over the past two decades has established that the livers of fish contain many of the same
metabolic pathways and enzymes known for mammalian liver (Cowey and Walton, 1982; Moon et al.,
1995); however, important differences exist (for more details, see Hinton et al., 2001). An important
difference between fish and mammalian liver with respect to toxicant action is the apparent absence of
a functional metabolic zonation. In the mammalian liver, storage products such as glycogen and lipid
as well as many metabolic enzymes are heterotopically distributed in the parenchyma. The distribution
patterns appear to be related to the direction of microvascularization. The capacity for oxidative metab-
olism (e.g., β-oxidation of fatty acids, amino acid catabolism, or oxidative energy metabolism) is higher
in the periportal than in the perivenous zone or centrolobular (zone 3 of the liver acinus model in
mammals) (Jungermann and Katz, 1989). Accordingly, the upstream cells show greater mitochondria
and larger cristae area than do the downstream cells (Loud, 1968). It is supposed that the concentration
gradients of oxygen, hormones, and substrates in the sinsusoidal bloodstream lead to the expression of
different enzyme levels in the bordering hepatocytes. The concept of metabolic zonation (Jungermann
and Katz, 1989; Teutsch, 1981) suggests that the biological significance of this functional heterogeneity
might be to enable the liver to perform antagonistic metabolic functions at the same time.
The distribution of enzymes and storage products within the liver parenchyma of fish has been
determined by enzyme histochemistry in frozen sections and by digitonin pulse infusion. For most
enzymes studied, histochemical investigations were not able to demonstrate a heterotopic distribution
in the liver parenchyma of fish (Burkhardt-Holm et al., 1993; Hampton et al., 1985; Schar et al., 1985;
Segner and Braunbeck, 1988) (Table 7.5). Glycogen phosphorylase is the only enzyme for which all
studies report a heterogeneous distribution in fish liver; however, it is not clear to what extent the observed
phosphorylase pattern is determined by, or associated with, the hepatic microvasculature.
To separate hepatocytes from sites adjacent the afferent vasculature from those adjacent the efferent
vasculature, a short pulse of cytotoxic digitonin from either the portal (anterograde) or hepatic vein
(retrograde) is used. Subsequently, cell isolates presumably enriched in periportal or perivenous liver cells
may be prepared and analyzed for their metabolic properties. For teleosts, such studies have been done
with rainbow trout (Oncorhynchus mykiss) (Mommsen et al., 1991), toadfish (Opsanus tau) (Mommsen
and Walsh, 1991), and catfish (Ictalurus melas) (Ottolenghi et al., 1991). None of the cited studies observed