Page 389 - The Toxicology of Fishes

Liver Toxicity 369

for both systemic and organ-specific toxicity. First, hepatic biotransformation directly relates to bioac-
cumulation of lipophilic substances in fish (Schultz and Hayton, 1999; Sijm et al., 1993; Stuthridge et
al., 1997). Second, hepatic metabolism influences the toxicity of xenobiotics either through effects on
tissue doses of the toxicant or through generation of metabolites with either reduced or enhanced toxicity
(detoxification/toxification) of the parent compound (Debruijn et al., 1993; Keizer et al., 1991; Lech and
Bend, 1980). Hepatic metabolism is also important in determining species differences in the bioaccu-
mulation (Schultz and Hayton, 1999) and toxicity (Hasspieler et al., 1994; Wirgin and Waldman, 2004)
of xenobiotics in fish.
For mammals, numerous studies have shown the relation between the tissue-specific formation of a
reactive intermediate and hepatotoxicity. Further differences in the distribution of xenobiotic-metaboliz-
ing enzymes among the particular liver cell types predispose them to xenobiotic toxicity. In fish a number
of studies have analyzed liver conversion of xenobiotics in fish; however, information relating hepatic
biotransformation to hepatotoxicity is often lacking. The distribution of metabolic enzymes such as
CYP1A in the different cell types of fish liver and their roles in subsequent development of liver toxic
lesions have received little attention, with the one exception being liver carcinogenesis (see chronic
biliary toxicity discussion in this chapter).
One group of environmental contaminants that fish are often exposed to and for which hepatic
metabolism is an important toxicokinetic and toxicodynamic determinant are polycyclic aromatic hydro-
carbons (PAHs) (Altenburger et al., 2003). Several studies have investigated the spectrum of metabolites
produced by fish liver preparations and found a high proportion of 7,8- and 9,10-dihydrodiols (Lemke
and Kennedy, 1997; Morrison et al., 1985; Nishimoto et al., 1992). Induction of metabolic enzymes,
however, can result in a shift of the metabolite spectrum (van Schanke et al., 2000). Information is
available from both field and laboratory studies on the association of exposure to PAHs, enhanced
expression of hepatic biotransformation enzymes, and the occurrence of DNA adducts and toxicopathic
liver lesions, including neoplastic alterations (Aas et al., 2001; Dey et al., 1993; James et al., 1988;
Lesage et al., 2001; Malins et al., 1988; Myers et al., 1987, 1994, 1998; Orsler et al., 1999; Palmeira et
al., 2003; Spitsbergen et al., 2000a,b; Vogelbein et al., 1999). In a field study on the Puget Sound, Horness
et al. (1998) were able to establish statistically significant threshold levels for the association of PAH
concentrations in the sediments and the occurrence of neoplastic liver alterations in flatfish, this providing
strong evidence for a causative role of hepatic PAH metabolism in carcinogenesis of the fish species.
Another example where hepatic metabolism of xenobiotics is an important determinant in toxicity is
related to the hepatocarcinogenic mycotoxin aflatoxin B . In the liver of trout, aflatoxin B is metabolized
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to aflatoxicol B and excreted as aflatoxicol B glucuronide (Loveland et al., 1984). An increase in
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metabolism of aflatoxin B and enhanced biliary excretion as glucuronide following pretreatment by the
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CYP1A inducers β-naphthoflavone or Arochlor 1254 significantly reduced liver DNA adduct formation
(Bailey et al., 1987). Further, pretreatment of trout with indole-3-carbonyl (an inducer of glutathione S-
transferase) also reduced the carcinogenicity of aflatoxin B (Goeger et al., 1986). Differences in aflatoxin
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metabolism are also likely to be responsible for the known differences in aflatoxin sensitivity between
rainbow trout and Coho salmon (Bailey et al., 1984; Coulombe et al., 1984). A contradictory example
appears to be the zebrafish, as adult zebrafish rapidly metabolize and excrete aflatoxin B . Both in vitro
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and in vivo studies indicate that this species has the capacity to bioactivate aflatoxin B to its reactive
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intermediate, and the level of hepatic DNA adducts is only moderately lower than observed in trout
(Troxel et al., 1997). An apparent contradiction to these findings is the reported resistance of zebrafish
when aflatoxin B was administered in the diet. It is possible that mechanisms other than biotransfor-
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mation protect the zebrafish against aflatoxin toxicity.
A further example where hepatic metabolism is at least partially responsible for chemical toxicity is
the procarcinogen 2-acetylaminofluorene (AAF), which induces liver tumors in fish at a much lower
rate than in rodents (James et al., 1994). This apparently higher resistance of fish to the hepatocarcino-
genicity of AAF seems to be related to AAF metabolism. For medaka, guppy, and trout, major metabolites
of AAF generated in the liver are hydroxy-AAFs, while the carcinogenic metabolite N-hydroxy-AAF is
formed at only low rates (James et al., 1994; Steward et al., 1994). Thus, the metabolic differences
between fish and mammals may partially explain the resistance of fish and susceptibility of mammals
to AAF-induced hepatocarcinogenesis.