2 Oxidative Stress, Geno- and Cytotoxicity
Reactive oxygen species (ROS) are generated in the mitochondria as a result of
cellular respiration; they are also produced as a result of the metabolic processes that
are carried out [7]. At normal physiological levels, they play a role in the regulation
of signaling pathways and gene expression, and therefore, their production is of vital
importance [8]. In addition, these species are formed during the biotransformation of
various drugs including NSAIDs [9], and among these ROS are the superoxide anion
radical (O 2 •
À ), its conjugate acid, the hydroperoxide radical (HO• 2 ), hydroxyl
radicals (OH•), and hydrogen peroxide (H 2 O 2 ) [10, 11]. The main enzymes that
catalyze the generation of ROS include nitric oxide synthase, NADPH oxidase,
prostaglandin synthase, xanthine oxidase, lipoxygenase, ribonucleotide reductase,
glucose oxidase, myeloperoxidase, cyclooxygenase, and cytochrome P450 [12, 13].
Oxidative stress (OS) is a biochemical imbalance between the production of
reactive species and antioxidant systems [8, 14]. Several studies have shown that
high levels of free radicals or ROS in conjunction with reactive nitrogen species such
as peroxynitrite anion (ONOO-), which is formed by reaction of nitric oxide that is
derived from metabolism of arginine with O 2 •, whose reaction is catalyzed by the
enzyme nitric oxide synthase [15, 16], generate damage to biomolecules such as
lipids, proteins, and DNA. ONOO- can also affect the state of cellular energy by
inactivating mitochondrial enzymes and can trigger the release of calcium from
mitochondria [8].
Lipid damage occurs in lipids that contain carbon-carbon double bonds, especially polyunsaturated fatty acids; additionally lipids can also be oxidized by
enzymes such as lipoxygenases, cyclooxygenases, and cytochrome P450. The
main primary products of lipid peroxidation are lipid hydroperoxides, and secondary
products are malondialdehyde (MDA), propanal, hexanal, and 4-hydroxynonenal,
which can modify membrane permeability [17–19], altering their fluidity and finally
inactivating membrane proteins. MDA is an important cytotoxic product and has a
high reaction capacity with multiple biomolecules such as proteins and DNA that
lead to adduct formation [17].
Proteins are also susceptible to oxidation by ROS; the main oxidative modifications of the protein occur in amino acid side chains, which include oxidation of the
thiol group, aromatic hydroxylation, and formation of carbonyl groups
[11, 20]. Besides, ROS can lead to the formation of protein-protein cross-links and
the oxidation of the main protein chain, resulting in protein fragmentation [10]. Cysteine and methionine are the most susceptible to oxidation because they contain
sulfur atoms which are very reactive [13].
To regulate excess ROS, the cell can (a) restrict breathing in the mitochondrial
compartment, thus protecting other cellular components, (b) protect DNA by
complexing it with histones, and (c) activate antioxidant enzymes [21–23]. Among
the latter are superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx), among others [9]. SOD catalyzes the conversion of O 2 •
À to H 2 O 2 ; the
DNA Alterations and Cellular Damage Induced by Non-steroidal. . .
107
Reactive oxygen species (ROS) are generated in the mitochondria as a result of
cellular respiration; they are also produced as a result of the metabolic processes that
are carried out [7]. At normal physiological levels, they play a role in the regulation
of signaling pathways and gene expression, and therefore, their production is of vital
importance [8]. In addition, these species are formed during the biotransformation of
various drugs including NSAIDs [9], and among these ROS are the superoxide anion
radical (O 2 •
À ), its conjugate acid, the hydroperoxide radical (HO• 2 ), hydroxyl
radicals (OH•), and hydrogen peroxide (H 2 O 2 ) [10, 11]. The main enzymes that
catalyze the generation of ROS include nitric oxide synthase, NADPH oxidase,
prostaglandin synthase, xanthine oxidase, lipoxygenase, ribonucleotide reductase,
glucose oxidase, myeloperoxidase, cyclooxygenase, and cytochrome P450 [12, 13].
Oxidative stress (OS) is a biochemical imbalance between the production of
reactive species and antioxidant systems [8, 14]. Several studies have shown that
high levels of free radicals or ROS in conjunction with reactive nitrogen species such
as peroxynitrite anion (ONOO-), which is formed by reaction of nitric oxide that is
derived from metabolism of arginine with O 2 •, whose reaction is catalyzed by the
enzyme nitric oxide synthase [15, 16], generate damage to biomolecules such as
lipids, proteins, and DNA. ONOO- can also affect the state of cellular energy by
inactivating mitochondrial enzymes and can trigger the release of calcium from
mitochondria [8].
Lipid damage occurs in lipids that contain carbon-carbon double bonds, especially polyunsaturated fatty acids; additionally lipids can also be oxidized by
enzymes such as lipoxygenases, cyclooxygenases, and cytochrome P450. The
main primary products of lipid peroxidation are lipid hydroperoxides, and secondary
products are malondialdehyde (MDA), propanal, hexanal, and 4-hydroxynonenal,
which can modify membrane permeability [17–19], altering their fluidity and finally
inactivating membrane proteins. MDA is an important cytotoxic product and has a
high reaction capacity with multiple biomolecules such as proteins and DNA that
lead to adduct formation [17].
Proteins are also susceptible to oxidation by ROS; the main oxidative modifications of the protein occur in amino acid side chains, which include oxidation of the
thiol group, aromatic hydroxylation, and formation of carbonyl groups
[11, 20]. Besides, ROS can lead to the formation of protein-protein cross-links and
the oxidation of the main protein chain, resulting in protein fragmentation [10]. Cysteine and methionine are the most susceptible to oxidation because they contain
sulfur atoms which are very reactive [13].
To regulate excess ROS, the cell can (a) restrict breathing in the mitochondrial
compartment, thus protecting other cellular components, (b) protect DNA by
complexing it with histones, and (c) activate antioxidant enzymes [21–23]. Among
the latter are superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx), among others [9]. SOD catalyzes the conversion of O 2 •
À to H 2 O 2 ; the
DNA Alterations and Cellular Damage Induced by Non-steroidal. . .
107