Stress, oxidative

Oxidative stress involves an imbalance between cellular reactive oxygen species (ROS) and antioxidant mechanisms that keep these in check. ROS include hydrogen peroxide (H202), superoxide anion radical (02- ), and the hydroxyl radical ( OH). 02 and OH are free radicals, that is, they possess an unpaired electron. As such, free radicals are extremely reactive and will seek an electron from nearby electron-rich macromolecules, for example, proteins, lipids, and DNA, which can lead to disruption of cellular functions. 

ROS are maintained at tolerable levels through the combined efforts of antioxidant mechanisms, which include both enzymes and nonenzymatic molecules. Important antioxidant enzymes include superoxide dismutases (SODs), catalases (CATs), peroxidases, and those maintaining reduced glutathione (GSH) levels. Nonenzymatic antioxidants include GSH, a tripeptide containing a cysteinamino acid, and vitamins, such as vitamin A, E, and C. 

H202 may also undergo homolytic cleavage of the peroxide catalyzed by transition metals, such as Fe2 +, Cu2 +, Mn2 +, Ni2 +, and Cr5 +, via the Fenton reaction, to produce the highly reactive OH radical and the hydroxyl anion (OH-). 

The outcome of oxidative stress is a depletion of cellular GSH, NADPH, NADH, and ATP, and also damage to lipid membranes, structural and enzymatic proteins, and DNA. 

Oxidative stress has increasingly been recognized as a key mechanism of DILI [83, 

Oxidative stress (OS) has been advanced to explain many of the hazardous effects of xenobiotic exposure including carcinogenesis. OS theory as it applies to particular xenobiotic impacts is addressed in succeeding chapters, which address the different target organs of foreign chemicals. The discussion here is an introductory one. The reader is referred to two articles in the literature and the references contained therein for a more comprehensive discussion. I5,6  

Metabolic processes in the body include reactions that have electron transfer (ET) associated with them. Most xenobiotics or their Phase I enzyme metabolites contain ET moieties. The principal groups include phenols, quinones, aromatic nitro compounds, amines, imines, and metal complexes or complexors. 

OS theory is based on the tenet that in vivo redox cycling with oxygen results in the formation of reactive oxygen species (ROS). OS is defined as the state where the body has excessive ROS. 

The radical nature of the oxygen molecule facilitates its reaction with various substrates to form radical species. Molecular oxygen can undergo a single electron reduction to form the superoxide (SO). SO can be converted in vivo to peroxides and various oxyradical species, including hydroxyl (OH), alkoxyl (RO), and peroxyl (ROO) radicals (Fig. 4.3). SO is usually disposed of in the body by enzymatic conversion to nonradical hydrogen peroxide (Fig. 4.4). 

Hydrogen peroxide, which has many metabolic functions in the body, can undergo the Fenton reaction to produce the hydroxyl radical, one of the most powerful ROS (Fig. 4.5). 

Arsenic has been shown to induce oxidative stress (Shi, Shi and Liu, 2004 Hughes and Kitchin, 2006). Oxidative stress is a result of an imbalance between reactive oxygen species and the ability of a cell s antioxidant defense apparatus to respond. Oxidative stress can result in the damage of proteins, lipids, RNA, and deoxyribonucleic acid (DNA). In addition, since oxidant species have a role in cell signaling, a state of oxidative stress could potentially alter signaling within and between cells. 

DNA isolated from cells (Kessel et al., 2002) and tissues and urine of animals (Vijayaraghavan et al., 2001 Yamanaka et al., 2001) treated with arsenic show lesions induced by oxidative stress. These lesions include 8-oxo-2 -deoxyguanosine and 8-hydroxy-2 -deoxyguanosine. These DNA lesions may lead to base-pair substitutions (guanine to thymidine and adenine to cytosine) during DNA synthesis, which could lead to altered gene products. 

The mechanism for arsenic-induced oxidative stress injury is not known with certainty. It may occur as a consequence of free radical production due to redox cycling of As(III) and As(V), release of iron from 

The loss of control of endogenous oxidative events in the use of molecular oxygen by the cell is the major factor in oxidative stress injury. Such a process, which is known as chemical-induced oxidative stress, may occur to an extent that ranges from a minor to a major contribution to overall toxicity. For example, chemicals that are known to undergo redox cycling cause exogenous oxidative stress to such a degree that they play a major role in chemically induced cell injury. In addition, some of these chemicals are known to form adducts with cellular constituents, particularly 

The most common type of primary liver tumor is hepatocellular carcinoma other types include cholangiocarcinoma, angiosarcoma, glandular carcinoma, and undifferentiated liver cell carcinoma. Although a wide variety of chemicals are known to induce liver cancer in laboratory animals (Table 14.1), the incidence of primary liver cancer in humans in the United States is very low. 

Some naturally occurring liver carcinogens are aflatoxin, cycasin, and safrole. A number of synthetic chemicals have been shown to cause liver cancer in animals, including the dialkylnitrosamines, dimethylbenzanthracene, aromatic amines such as 

Sites of blocking oxidant challenges by antioxidant defenses. 

2-naphthylamine and acetylaminofluorene, and vinyl chloride. The structure and activation of these compounds can be found in Chapters 7 and 8. In humans, the most noted case of occupation-related liver cancer is the development of angiosarcoma, a rare malignancy of blood vessels, among workers exposed to high levels of vinyl chloride in manufacturing plants. For a discussion of chemical carcinogenesis, see Chapter 12. 

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I. Tomita and co-workers, iu R. G. Cuder and co-workers, eds.. Oxidative Stress and Aging, Birkhauser Vedag, Basel, Swit2edand, pp. 355—365, 1995. 

Loikkanen, J., Naarala, J., and Savolainen, K. M. (1998). Modification of glutamate-induced oxidative stress by lead The role of extracellular calcium. Free Rad. Biol. Med., 24, 377-384,... 

Savolainen, K. M., L,oikkanen, J., Eerikainen, S., and Naarala, J. (1998). Interactions of excita-rury neurotransmitrers and xenobiorics in excitoroxiciry and oxidative stress Gliiraroare and lead. Toxicol. Lett. 102-103, 363-367. 

Cotton, B., Allshire, A., Cobbold, P. H., Muller, T., and Campbell, A. K. (1989). Pholasin a novel bioluminescent probe for monitoring oxidative stress in single cardiomyocytes. Biochem. Soc. Trans. 17 705-706. 

P450 Mono-oxygenase System Reactive Oxygene Species Oxidative Stress Vitamin C Vitamin E... 

Nifurtimox, a nitrofuran, is a prodrug that is reduced to unstable nitroanion radicals, which react to produce highly toxic oxygen metabolites, such as superoxide and peroxide. Oxidative stress subsequently kills the parasite, which seems to lack effective enzymatic pathways to detoxify oxygen metabolites. 

Oxidative stress has received much attention as a potentially pathogenic factor. It may promote COPD by many factors such as induction of pro-inflammatory genes in many cells including epithelial and endothelial... 

Reactive Oxygen Species Antioxidants Oxidative Stress... 

It has been proposed that the development of the complications of diabetes mellitus may be linked to oxidative stress and therefore might be attenuated by antioxidants such as vitamin E. Furthermore, it is discussed that glucose-induced vascular dysfunction in diabetes can be reduced by vitamin E treatment due to the inactivation of PKC. Cardiovascular complications are among the leading causes of death in diabetics. In addition, a postulated protective effect of vitamin E (antioxidants) on fasting plasma glucose in type 2 diabetic patients is also mentioned but could not be confirmed in a recently published triple-blind, placebo-controlled clinical trial [3]. To our knowledge, up to now no clinical intervention trials have tested directly whether vitamin E can ameliorate the complication of diabetes. 

As the above mentioned studies with high supplementation dosages exemplarily show, there is no known toxicity for phylloquinone (vitamin Kl), although allergic reactions are possible. This is NOT true for menadione (vitamin K3) that can interfere with glutathione, a natural antioxidant, resulting in oxidative stress and cell membrane damage. Injections of menadione in infants led to jaundice and hemolytic anemia and therefore should not be used for the treatment of vitamin K deficiency. 

When considering the role of phosphorylation in the regulation of the HS response, it is indeed curious that oxidative stress and heat induce a protein tyrosine phosphatase at the transcriptional level (Keyse and Emslie, 1992). Whether this phosphatase has any role in the regulation of HSF phosphorylation is not known, but it does indicate that both transcriptional and translational regulation of signaling... 

Christman, M.F., Morgan,R.W., Jacobson, F.S., Ames, B. (1985). Positive control of a regulon for defenses against oxidative stress and some heat shock proteins in Salmonella typhimurium. Cell 41, 753-762. 

Keyse, S.M. Emslie, E.A. (1992). Oxidative stress and heat shock induce a human gene encoding a protein-tyrosine phosphatase. Nature 359, 644-647. 

Salo, D.C., Donovan, C.M., Davies, K.J, (1991). Hsp70 and other possible heat shock or oxidative stress proteins are induced in skeletal muscle, heart, and liver during exercise. Free Radic. Biol. Med 11,239-246. 

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