Abstract
In order to assess the cause of the resistance of rainbow trout ( Oncorhynchus mykiss), Shasta strain, to the hepatocarcinogenic effects of 2-acetylaminofluorene (AAF), we have investigated the metabolism of this model chemical by subcellular fractions from trout liver. Treatment of trout with 3-methylcholanthrene (3-MC) enhanced the rate of metabolism of AAF by liver microsomes. The major AAF metabolites produced by trout liver microsomes at saturating substrate concentration (34.3 and 19.5 μM AAF for control and 3-MC-induced microsomes, respectively) were 7-hydroxy-AAF and 5-hydroxy-AAF which represented 75 and 21% of total AAF metabolites, respectively for control microsomes, and 79 and 18% of total metabolites, respectively for induced microsomes. With both control and 3-MC-induced microsomes, N-hydroxy-AAF (the proximate carcinogen of AAF) was a minor metabolite accounting for less than 1% of total AAF metabolites. At a low substrate concentration (0.18 μM AAF), 7-hydroxy-AAF formation accounted for 95 and 91% of total metabolites for control and 3-MC induced microsomes, respectively, and a slight relative increase in N-hydroxy-AAF production (1.5–2.5%) was observed. Liver microsomes from untreated male Sprague-Dawley rats (a species susceptible to hepatocarcinogenesis by AAF) formed N-hydroxy-AAF in greater proportions (14-fold) and ring-hydroxylated metabolites in smaller proportions compared to trout liver microsomes. The activities of cytosolic N-hydroxy-AAF sulfotransferase and acyltransferase in trout liver (24 and 17 pmol/mg h −1, respectively) were found to be substantially lower than those reported for Sprague-Dawley rats. The low activity of hepatic enzymes implicated in the metabolic activation of AAF (AAF-N-hydroxylase, N-hydroxy-AAF-sulfotransferase, and N-hydroxy-AAF acyltransferase) coupled with a relatively high capacity of the trout liver for ring-hydroxylation (detoxification) of AAF may explain, in part, the resistance of rainbow trout to the hepatocarcinogenic action of AAF.
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