No abstract

A radical is any molecule that contains one or more unpaired electrons. Radicals are normally generated in many metabolic pathways. Some of these radicals can exist in a free form and subsequently interact with various tissue components resulting in dysfunction. The potential role of oxygen- or xenobiotic-derived free radicals in the pathology of several human diseases has stimulated extensive research linking the toxicity of numerous xenobiotics and disease processes to a free radical mechanism. However, because free radical-mediated changes are pervasive and often poorly understood, the question of whether such species are a major cause of tissue injury and human disease remains equivocal. This review discusses cellular sources of various radical species and their reactions with vital cellular constituents. Examples of purported free radical-mediated disorders are discussed in detail to provide insights into the controversy over whether free radicals are important mediators of tissue injury.

Acrolein is a highly electrophilic alpha,beta-unsaturated aldehyde to which humans are exposed in a variety of environmental situations, particularly as a component of smoke. In addition, as a metabolite of cyclophosphamide, acrolein is a major factor in the toxicity and perhaps the therapeutic activity of this important anticancer agent. The exposures to acrolein that are attained in vivo in most situations are quite low and the effects may differ from those seen at acutely toxic doses. At low doses, acrolein inhibits cell proliferation without causing cell death and may enhance apoptosis from secondary toxins, while at higher doses oncosis ensues. Although the acute toxicology of acrolein has been extensively investigated, both in animals and cultured cells, little information exists on the molecular effects of this reactive aldehyde. It is possible that the acrolein-mediated decrease in cell proliferation is caused by effecting changes in the expression of one or more growth- or stress-related genes or transcription factors secondary to a reduction in glutathione (GSH), which is rapidly depleted following acrolein treatment. It is apparent that the activation of the transcription factors nuclear factor kappa B (NF-kappa B) and activator protein 1 (AP-1) can be inhibited by acrolein. The purpose of this review is to assess the literature currently available on the molecular effects of acrolein, to discuss the relationship between effects on glutathione with those on various genes, and to present some new data showing that acrolein actively stimulates genes associated with the electrophile response element.

A radical is any molecule that contains one or more unpaired electrons. Radicals are normal products of many metabolic pathways. Some exist in a controlled (caged) form as they perform essential functions. Others exist in a free form and interact with various tissue components. Such interactions can cause both acute and chronic dysfunction, but can also provide essential control of redox regulated signaling pathways. The potential roles of endogenous or xenobiotic-derived free radicals in several human pathologies have stimulated extensive research linking the toxicity of numerous xenobiotics and disease processes to a free radical mechanism. In recent years, improvements in analytical methodologies, as well as the realization that subtle effects induced by free radicals and oxidants are important in modulating cellular signaling, have greatly improved our understanding of the roles of these reactive species in toxic mechanisms and disease processes. However, because free radical-mediated changes are pervasive, and a consequence as well as a cause of injury, whether such species are a major cause of tissue injury and human disease remains unclear. This concern is supported by the fact that the bulk of antioxidant defenses are enzymatic and the findings of numerous studies showing that exogenously administered small molecule antioxidants are unable to affect the course of most toxicities and diseases purported to have a free radical mechanism. This review discusses cellular sources of various radical species and their reactions with vital cellular constituents, and provides examples of selected disease processes that may have a free radical component.

Thioredoxins (Trx) are members of an evolutionarily conserved family of redox-active proteins containing a conserved active site dithiol motif. Trx supports diverse reduction reactions, including several of direct toxicologic interest, but relatively little information is available concerning the roles of Trx under specific toxicologic conditions. Accumulating evidence suggests that Trx serves a partially overlapping and highly complementary role to the glutathione (GSH) system in protecting against toxicity. GSH and Trx both function in the reduction of peroxides through the action of multiple GSH peroxidases and Trx peroxidases (peroxiredoxins), respectively. However, GSH is a small molecule that is present at millimolar concentrations, thereby providing a potential mechanism for elimination of alkylating electrophiles. In contrast, even though Trx is only present at micromolar or submicromolar concentrations, its dithiol motif makes it suited to reverse oxidative changes to proteins, including reduction of protein disulfides, methioninyl sulfoxides, and cysteinyl sulfenic acids. Moreover, Trx functions in redox-sensitive signal transduction, transcriptional activation of stress response genes, ribonucleotide reduction in synthesis of deoxyribonucleotides for DNA repair, and post-injury cell proliferation. Molecular studies show that the predominant cytoplasmic/nuclear form, Trx-1, and the mitochondrial form, Trx-2, both protect against oxidative stress, that both are essential for embryonic development, and that Trx-1 is inducible in response to oxidative stress. Because of the differences between GSH and Trx in distribution, catalytic activities and reactivities with electrophiles, particularly with the important role to be played by glutathione S-transferases, considerable research is needed to clarify their respective roles in protection against specific toxicologic conditions.