Xenobiotics oxidative stress

C. L. Crowley-Weber, K. Dvorakova, C. Crowley, H. Bernstein, C. Bernstein, H. Garewal and C. M. Payne, Nicotine increases oxidative stress, activates NF-kappaB and GRP78, induces apoptosis and sensitizes cells to genotoxic/xenobiotic stresses by a multiple stress inducer, deoxy-cholate relevance to colon carcinogenesis, Chem. Biol. Interact., 2003, 145(1), 53. 

Pedrajas, J.R., J. Peinado, and J. LopezBarea. 1995. Oxidative stress in fish exposed to model xenobiotics. Oxidatively modified forms of Cu, Zn superoxide dismutase as potential biomarkers. Chem. Biol. Interact. 98 267-282. 

Transcription is activated by xenobiotic metabolites and oxidative stress. 

Figure 20.9. Protective and toxic signal balance in xenobiotic metabolism and generation of oxidative stress.

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]. 

Glutathione (GSH Fig. 4.2), is perhaps the most important of the Phase II enzymes in the biotransformation and elimination of xenobiotics. It also defends cells against oxidative stress (see later). 

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 ... 

The question of whether RF (microwave range) and ELF radiation alone is toxic to humans remains an open question. What seems clear is that coexposure of electromagnetic radiation at virtually all frequencies with xenobiotic chemicals increases free radical formation and oxidative stress, with corresponding health consequences. 

Nutrition is a factor gaining more and more importance in terms of oxidative stress. Besides the known protective effects of healthy nutrition (see below), it can also be responsible for arising oxidative stress. Nutrition is not strictly an environmental noxa itself but it represents a blend of several noxae (e.g. radioactive isotopes, particulate matter, nitric oxides). Pre-noxae, primarily less or not dangerous, can be modified by the organism (e.g. via cytochrome P450 systems) and represent a major factor in oxidative stress induced by nutrition. Such modification, as in the xenobiotic metabolism, might lead to potential sources for oxidative stress. 

Activation of drugs to give toxic products is common. Apart from non-enzymatic activation (e.g., via autoxidation), activation by enzymatic one-electron oxidation or reduction frequently occurs. Several non-specific oxidases and reductases are encountered in mammalian tissues. Enzyme systems that have been studied in detail are peroxidases and microsomal oxidases and reductases. Xanthine oxidase also has received some attention. In many insta .ces the end products of the reaction are critically dependent upon the presence of oxygen in the system. This is because oxygen is an excellent electron acceptor, i.e., it can oxidize donor radicals, forming superoxide in the process. In this way a redox cycle is set up in which the xenobiotic substrate is recovered. The toxic effects of the xenobiotic often can be attributed to the oxidative stress arising from such a cycle. However, it seems that for some substrates, oxidative stress of this kind can be less damaging than anaerobic reduction. Anaerobic reduction can lead to formation of further reduced products with additional toxicity. 

Oxidative stress can be caused by a wide variety of factors, including inflammatory responses to infections or immune activation, exposure to heavy metals or toxic substances (Carpenter et al., 2002), and oxidative stress increases during the natural course of aging (Junqueira et al., 2007). When oxidative stress is induced by environmental exposures it represents a significant component of the toxicity syndrome, and most xenobiotics share the ability to cause oxidative stress. As a consequence, the effects of multiple exposures are additive at the level of oxidative stress. Metabolic changes associated with oxidative stress can be considered to be adaptive responses that increase prospects for survival during these stressful episodes. 

---