Page 302 - The Toxicology of Fishes

282 The Toxicology of Fishes

O
2 O•
(e.g., NADPH–P450 reductases) OH O –
1e-reductases
–
O 2

O Semiquinone radical
metabolite

OH O Quinone reductase OH
2e
Juglone –

Hydroquinone OH OH Conjugating systems O H
metabolite
+R

OH O R
Phase II
conjugates

Excretion
FIGURE 6.2 Metabolism of the plant-derived quinone juglone. Upper right portion depicts redox cycling through the
semiquinone radical intermediate, a one-electron reduction product. The lower pathway depicts the two electron reduction
pathway, which can be catalyzed by DT diaphorase (NAD(P)H:quinone oxidoreductase). This pathway yields phenolic
compounds that are readily detoxified by phase II pathways (see Chapter 4).

Quinone Reductases
Quinone reductases do not directly act on ROS; however, by reducing quinones they can diminish ROS
that are generated by quinones during the process of redox cycling, described below. Because quinones
comprise an important group of environmental contaminants (as well as natural products), the inclusion
of quinone reductase here is warranted (although it is also grouped with phase II enzymes, described in
Chapter 4). Quinones, such as the natural product juglone (Figure 6.2), can exert toxicity via two
mechanisms: reactions with –SH groups of GSH and proteins, leading to GSH depletion and enzyme
inactivation, for example, and through generation of ROS via redox cycling (Bolton et al., 2000; Dinkova-
Kostova and Talalay, 2000).
In the process of redox cycling, quinones can gain an electron from a reduced source, such as
NADPH–cytochrome P450 reductase (see Chapter 4), yielding a semiquinone radical (Figure 6.2). Under
•–
aerobic conditions, this radical can donate its unshared electron to O , producing O . Quinone reductases
2
2
circumvent this process by catalyzing a two-electron reduction of the quinone to its corresponding
hydroquinone. In addition to quenching ROS formation, the hydroquinone products thus formed are
oftentimes excellent substrates for phase II enzymes, particularly sulfotransferases (ST) and UDP-glucu-
ronosyltransferase (UGT) (see Chapter 4); thus, quinone reductase activity also enhances elimination.
In mammals, two distinct quinone reductases have been identified; both are primarily cytosolic and
both contain FAD (Foster et al., 2000). Until recently, only one had been recognized; it is formally
termed NAD(P)H:quinone oxidoreductase and is also referred to as DT diaphorase. Zhao et al (1997),
through comparisons with a cDNA clone isolated by Jaiswal (1994a), demonstrated that a previously
ignored protein with quinone reductase activity (described by Liao and Williams-Ashman, 1961) had
close sequence homology to DT diaphorase. This “rediscovered” protein structurally resembles a trun-
cated version of DT diaphorase but is a separate gene product. These enzymes are now oftentimes