Figure 1 Some reasons why tissue injury causes oxidative stress.
I. OXIDATIVE STRESS IN DISEASE: DOES IT MATTER?
The term oxidative stress is widely used in the literature but rarely defined. In essence, it refers to the situation of a serious imbalance between production of ROS/RNS/RCS and antioxidant defense. Sies, who introduced the term from the title of the book he edited in 1985, introduced a somewhat vague definition in 1991 in the introduction to the second edition (9) as a disturbance in the pro-oxidant-antioxidant balance in favor of the former, leading to potential damage.
In principle, oxidative stress can result from two mechanisms:
1. Diminished antioxidants, for example, mutations affecting antioxidant defense enzymes (such as CuZnSOD, MnSOD, and glutathione peroxidase) or toxins that deplete such defenses. For example, many xenobiotics are metabolized by conjugation with GSH; high doses can deplete GSH and cause
Table 1 Criteria for Implicating Reactive Oxygen/Nitrogen/Chlorine Species or
Any Other Agent as a Significant Mechanism of Tissue Injury in Human Disease
1. The agent should always be present at the site of injury.
2. Its time course of formation should be consistent with the time course of tissue injury.
3. Direct application of the agent to the tissue at concentrations within the range found in vivo should reproduce most or all of the damage observed.
4. Removing the agent or inhibiting its formation should diminish the injury to an extent related to the degree of removal of the agent or inhibition of its formation.
oxidative stress even if the xenobiotic is not itself a generator of ROS or RNS. Depletions of dietary antioxidants and other essential dietary constituents can also lead to oxidative stress.
2. Increased production of ROS/RNS/RCS, for example, by exposure to elevated 02, the presence of toxins that are themselves reactive species (e.g., N02") or are metabolized to generate ROS/RNS/RCS, or excessive activation of "natural" ROS/RNS/RCS-producing systems (e.g., inappropriate activation of phagocytic cells in chronic inflammatory diseases, such as rheumatoid arthritis and ulcerative colitis).
Mechanism 2 is usually thought to be more relevant to human diseases and is frequently the target of attempted therapeutic intervention but rarely is much attention paid to the antioxidant nutritional status of sick patients (e.g., Ref. 10). For example, calculations show that diabetic patients on fat-restricted diets may sometimes have a suboptimal intake of vitamin E (11). Prolonged oxidative stress can lead to depletion of essential antioxidants. For example, subnormal plasma ascorbate levels are well known in diabetics (12,13). There are conflicting views on whether diabetic patients show depleted plasma vitamin E levels, but data of Nourooz-Zadeh et al. (14) show a clear decrease in lipid standardized a-tocopherol levels in diabetic patients (Table 3), although there is considerable variability between patients, as indicated by the ranges in Table 3. It is possible that variations in dietary intake can account for some of the different results reported in the literature.
In principle, the onset of oxidative stress can result in adaptation, tissue injury, or cell death. Adaptation, most often by upregulation of defense systems, may completely protect against damage; protect against damage, but not completely; or "overprotect," for example, the cell is then resistant to higher levels of oxidative stress imposed subsequently. As an example of not completely protecting against damage, if adult rats are gradually acclimatized to
Table 2 Reactive Species
ROS Superoxide, 02'" Hydroxyl, OH' Peroxyl, R02" Alkoxyl, RO' Hydroperoxyl, H02' RNS
Nitric oxide (nitrogen monoxide), NO' Nitrogen dioxide, NO;"
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