Page 316 - The Toxicology of Fishes

296 The Toxicology of Fishes

Natural Products
The Gram-negative bacterium Pseudomonas aeruginosa can cause pneumonia via secretion of two
•–
compounds: procyanin and pyochelin (5-methyl-1-hydroxyphenazine). Procyanin generates O via
2
redox cycling (described in the following section), and pyochelin is a siderophore that binds iron and
promotes Fenton-chemistry-like generation of ·OH (Britigan et al., 1992). Juglone (5-hydroxy-1,4-
naphthoflavone; see Figure 6.2) and plumbagin (5-hydroxy-3-methyl-1,4-naphthoflavone) are redox-
cycling quinones produced by walnut trees (Juglans spp.). They suppress germination and growth of
other plant species (hence, the term allelotoxins), and their use in cosmetics has raised concerns for
human health (Inbaraj and Chignell, 2004; Seguraaguilar et al., 1992). In part, the hepatotoxicity of
ethanol, a byproduct of glucose metabolism by yeast, is believed to be associated with ethanol-mediated
induction of cytochrome P4502E1 (CYP2E1) and a resulting shift in ethanol metabolism to include a
greater contribution by CYP2E1 vs. the dominant pathway (alcohol and acetaldehyde dehydrogenases).
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CYP2E1 is a relatively leaky P450, and substantial O and H O are generated as a result of its activity,
2
2
2
which can thereby contribute to oxidative stress in the liver during chronic ethanol exposure (Caro and
Cederbaum, 2004).
Drugs
The deleterious side effects of some drugs are associated with oxidative stress. The liver and kidney
damage produced by high dosages of the common pain reliever acetaminophen occurs via GSH depletion
by the drug and a CYP2E1 metabolite (N-acetyl-p-benzoquinone) and accompanying effects on calcium
metabolism (Moore et al., 1985). Acetaminophen has been used frequently in suicide attempts, under-
scoring its toxic nature at high doses. The common urinary tract antibacterial nitrofurantoin is a nitroar-
omatic, and both its bactericidal activity and major deleterious side effect (lung damage) are thought to
be due to ROS generation via redox cycling through a nitro radical intermediate (Suntres and Shek, 1992).
A number of antibiotics, such as penicillins, natamycin, tetracyclines, streptonigrin, and gentamicin,
have been shown capable of generating ROS that are believed to underlie the tissue damage that
sometimes accompanies their use (Halliwell and Gutteridge, 1999). The addictive recreational drug
cocaine is a hepatotoxicant and neurotoxicant that is thought to act in part via ROS-generating reactive
metabolites (Boelsterli and Goldin, 1991), as well as through vasoconstriction that can also exert oxidative
stress, as indicated by elevated oxidations of glutathione and α-tocopherol (Lipton et al., 2003).

Environmental Pollutants
Numerous environmental pollutants have been demonstrated to impact organismal health via oxidative
stress; several illustrative examples are described here. Carbon tetrachloride (CCl ) is a common solvent
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and intermediate in the production of other chemicals and was the first environmental toxin to be shown
to exert toxicity through a free radical mechanism. Many of its uses, including as a solvent and cleaning
agent, have declined since the 1970s due largely to its great potency as a hepatic and renal toxicant, as
well as its carcinogenicity and contributing to stratospheric ozone depletion (ATSDR, 1994). Its toxicity
is based on its conversion by cytochrome P450s, particularly CYP2E1, to a trichloromethyl radical
•
(CCl ) (Recknagel et al., 1989; Zangar et al., 2000). This radical can bind to proteins and lipids directly
3
and also react with O to produce the thrichloromethylperoxyl radical (Cl COO ). Both processes lead
•
2
3
2+
to extensive membrane damage, including lipid peroxidation, and can lead to elevated intracellular Ca ,
an important component of CCl cytotoxicity (Stoyanovsky and Cederbaum, 1996).
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Benzene is a ubiquitous contaminant used as a precursor for various products; benzene is particularly
toxic to mammalian bone marrow, and epidemiological studies indicate that elevated exposures cause
leukemias in humans, as well as other cancers (Snyder, 2002). The metabolism of benzene to toxic
intermediates is also initiated by cytochrome P450s, particularly CYP2E1, which yield various phenols.
These phenols are distributed to various tissues, where additional metabolism can yield highly redox-
active quinones via the action of various peroxidases, such as myeloperoxidase, which is highly enriched
in bone marrow. Quinones comprise a large set of reactive intermediates of numerous compounds,
including PAHs, estrogens, and catecholamines, that have been shown collectively to produce acute