Page 199 - The Toxicology of Fishes

Biotransformation in Fishes 179

Peroxidases
Lipoxygenases, cyclooxygenases, and peroxidases such as prostaglandin-H synthetase are typically
involved in the oxidation of arachidonic acid to hydroxy and peroxyeicosatetraenoic acids, which are
subsequently converted to prostaglandins, prostacylins, and thromboxanes. In mammals, each of these
enzymes has been shown to activate various xenobiotics through cooxidation pathways requiring a
hydroperoxide as a cofactor. Although the enzymes have been observed in fish, their contributions to
xenobiotic biotransformation has not been examined. Examples of lipoxygenases observed in rainbow
trout gills include the 15- and 12-lipoxygenase (German and Berger, 1990; Hsieh et al., 1988). PGH
synthetase has also been observed in gills of freshwater fish (Christ and Van Dorp, 1972).

Aldehyde Oxidase
Aldehyde oxidase is a molybdozyme that is similar to xanthine oxidase located in the cytosols of liver
in mammals and fish. Pyrroles, pyridines, pyrimidines, purines, and aromatic aldehydes derived from
catecholamine metabolism tend to undergo oxidation reactions; however, under anaerobic conditions,
1
2-hydroxypyrimidine, N -methylnicotinamide, or butyraldehyde may act as electron donors in liver
cytosols in fish, leading to substrate reduction under these conditions. Enzyme activity is inhibited by
menadione, β-estradiol, and chlorpromazine. Recent studies in the goldfish (Carassius auratus) and the
sea bream (Pagrus major) have demonstrated that aldehyde oxidase catalyzes the reduction of fenthion
sulfoxide to the parent sulfide (Kitamura et al., 2003).

Reductases
One of the most common reductases involved in xenobiotic biotransformation is the cytochrome P450
reductase, which catalyzes single-electron reductions to substrates prone to accept single electrons (e.g.,
quinones, cyclic or aromatic amines). Often, this pathway activates heterocyclic compounds to redox
cycling intermediates. Limited studies have evaluated the role of this enzyme in biotransformation in
fish.

DT Diaphorase
DT diaphorase (NAD(P)H:[quinone acceptor] oxidoreductase) plays a significant role in one- and two-
electron reduction reactions, particularly in the liver. 4-Nitroquinoline 1-oxide and nitrofurantoin were
both reduced by DT diaphorase to genotoxic metabolites in a brown bullhead fibroblast cell line
(Hasspieler et al., 1997). A novel dicoumarol-sensitive oxidoreductase that catalyzes the reduction of
phenanthrenequinone was purified from gastric cytosol in the channel catfish (Ictalurus punctatus)
(Hasspieler and Di Giulio, 1994). Due to its likely AhR-mediated regulation, the enzyme has shown
promise as a biomarker in fish (see Chapter 16). Whether or not bifunctional regulation through ARE
occurs (as in mammals) is uncertain.

Azo- and Nitroreductases
Catalyzing up to three sequential two-electron reductions, nitroreductases play a significant role in the
biotransformation of primarily nitroaromatic compounds to corresponding amino aromatic compounds.
When 2-nitrofluorene was incubated with liver microsomes or cytosol of sea bream (Pagrus major) in
the presence of NADPH or 2-hydroxypyrimidine, 2-aminofluorene was formed (Ueda et al., 2002).
Hepatic nitroreductases were also observed in catfish and catalyzed the formation of superoxide from
nitrofurantoin, p-nitrobenzoic acid, and m-dinitrobenzene (Washburn and Di Giulio, 1988). Hepatic nitro-
and azoreductases were observed in the marine teleosts barracuda (Sphyraena barracuda) and yellowtail
snappers (Ocyurus chrysurus); however, only azoreductase activity was observed in elasmobranches,
such as the lemon shark (Negaprion brevirostris) and stingray (Dasyatis americana) (Adamson et al.,
1965). The lampricide 3-trifluoromethyl-4-nitrophenol was reduced by nitroreductases to 3-trifluoro-
methyl-4-aminophenol in rainbow trout (Lech and Costrini, 1972).