Bioactivation oxidative stress

Phytochemicals or phytonutrients are bioactive substances that can be found in foods derived from plants and are not essential for life the human body is not able to produce them. Recently, some of their characteristics, mainly their antioxidant capacity, have given rise to research related to their protective properties on health and the mechanisms of action involved. Flavonoids are a diverse group of phenolic phytochemicals (Fig. 6.1) that are natural pigments. One function of flavonoids is to protect plants from oxidative stress, such as ultraviolet rays, environmental pollution, and chemical substances. Other relevant biological roles of these pigments are discussed in other chapters of this book. 

In addition to oxygen free radicals, other compounds such a clozapine, olanzapine and procainamide induce reactive intermediates [8, 9]. Clozapine and olanzapine bioactivation is thought to occur through a nitrenium ion [20] however clozapine but not olanzapine induce toxicity to neutrophils. This can lead to an immune-mediated depletion of neutrophils and their precursors (CFU-GM) [21]. Also, nonsteroidal antiinflammatory drugs (NSAIDs) have pro-oxidant radicals that when metabolized could cause oxidative stress [22]. 

Although GSH is found in many tissues, it is most abundant in the liver, where GSH levels may reach levels of 5mM or more [42]. GSH is maintained in the millimolar range by de novo synthesis and regenerative reactions however, levels may be severely depleted in times of oxidative stress, for example., as mentioned above in the case of acetaminophen (APAP) overdose and bioactivation, which leaves cellular proteins vulnerable to attack by electrophiles and free radicals. 

However, the adverse effects of APAP bioactivation are not observed until high doses are administered, where there is sufficient depletion of natural reserves of antioxidants, for example, reduced glutathione (GSH). Depletion of GSH exacerbates arylation of cellular proteins by NAPQI and amplifies oxidative stress from ROS, eventually leading to a drop in cellular ATP levels and cell death. Hence it is not the advent of covalent binding of reactive intermediates that is solely responsible for APAP toxicity, but rather a combination of events in which protein binding plays an important role. 

Thomas SR, Chen K, Keaney JF, Jr. Oxidative stress and endothelial nitric oxide bioactivity. Antioxid Redox Signa 2003 5 181-194. 

Ascorbic Acid (AA). Experimental (SI, S7, S24) and clinical (B13, B17) studies have provided some evidence for the concept that oxidative stress is the common pathway for the initiation of AP (B14). The most abundant endogenous antioxidant in the aqueous phase is ascorbic acid (AA), a bioactive form of vitamin C, which scavenges oxygen-derived free radicals produced by activated neutrophils and the hypoxanthine-xanthine oxidase system (D12). Scott et al. 

Depletion of cellular GSH has been widely studied with hundreds of chemicals including APAP and bromobenzene. These studies demonstrated very clearly that bioactivation followed by GSH adduct formation causes depletion of cytosolic glutathione and oxidative stress as indicated by indicators including enhanced levels of GSSG, lipid peroxidation, and loss of membrane integrity. 

A prooxidant is an agent that can induce oxidative stress, which is defined as a shift in the prooxidant-antioxidant balance toward oxidant activity. Oxidative stress induced by a prooxidant in a biological system manifests itself as increased production of bioactive free radical species, a decrease or modulation of antioxidant defenses, and/or an increase in oxidative damage. The fine balance between the oxygen center radicals and antioxidants may be dependent on the concentration of prooxidant, oxygen tension, and interactions with other antioxidants. 

It has been shown that the renal bioactivation of xenobiotics such as the herbicides paraquat and diquat [10, 111, 112], and of p-lactams such as cephaloridine and cefsulodin [10, 40, 41] or the antitumor agent adriamycin [113, 114] can induce the generation of reactive oxygen species (oxidative stress) which can be involved in alterations of the structure and functions of cell membranes, cytoskeletal injury, mutagenicity, carcinogenicity, and cell necrosis [115-117]. 

It is widely believed that oxidative stress (OS) is critical to carcinogenesis. OS theory states that bioactive agents (or their metabolites) that incorporate... 

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