Redox-Genome Interactions in Health and Disease

Jörgen Fuchs, Maurizio Podda, Lester Packer, Jörgen Fuchs, Maurizio Podda, Lester Packer

• Publisher: CRC Press
• Year: 2003
• ISBN:
  9781135526696
• Edition: 1
• Topic: Médecine
• Subtopic: Nutrition, diététique et bariatrie

At the nexus of advances in molecular genetics and findings in redox biology, this volume elaborates on the dynamics governing cellular redox states and aggregates the body of evidence linking oxidative stress and redox modulation with a host of monogenetic and polygenetic diseases.

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Redox-Genome Interactions: Evolution of a Concept

JÜRGEN FUCHS, MAURIZIO PODDA, and R.KAUFMANN

J.W.Goethe University, Frankfurt, Germany
LESTER PACKER

University of Southern California School of Pharmacy, Los Angeles, California, U.S.A.

Exciting new information in the field of genomics and proteomics is currently revolutionizing our understanding of cell biology and is providing new insights into the pathophysiology of human diseases. At the same time, an exponentially increasing interest in redox modulation of cell function, including gene regulation and gene expression, is evolving. There is a rapid if not explosive growth in the identification of signal transduction processes and regulatory elements found to be influenced by redox changes. The developments in these different but connected research areas create a new global perspective of redox-genome biology. An introduction to and overview of this exciting field of redox biology follows.

I. FREE RADICALS AS BIOCHEMICAL ENTITIES AND DAMAGING SPECIES

Two recent reviews present excellent overviews of past and present free radical research in biology and medicine [1, 2]. The first discovery of solution phase reactive oxygen chemistry is attributed to Fenton, who studied iron/hydrogen peroxide chemistry [3], whereas Gomberg in 1900 demonstrated the existence of an organic free radical. Radiation chemistry studies, beginning in the early twentieth century, led in 1954 to the discovery that free radicals are the molecular basis for oxygen toxicity [4]. The work of Weiss in the 1930s on metal-catalyzed peroxide decomposition, particularly with Haber [5, 6], and discoveries in radiation chemistry research had implications far beyond traditional free radical chemistry. Free radicals were accepted as chemical entities by biological scientists in the 1950s. Early studies focused mainly on free radicals bound to macromolecules, such as melanin radicals and protein-bound flavin semiquinone radicals. Stanford Moore and William Stein were awarded the Nobel Prize in chemistry in 1972 for their contribution to the understanding of the connection between chemical structure and catalytic activity of the active free radical center of ribonuclease, which catalyzes production of deoxyribonucleotides for DNA synthesis. It is interesting to note that several decades were required before solution phase oxy-radicals were widely accepted as credible biochemical entities [1]. The measurement of free radicals in biological samples was hampered for a long time due to restrictions in bioanalytical methodologies, thus the development of the electron paramagnetic resonance (EPR) spectrometer by Zavoisky in 1945 was a technological breakthrough [7]. EPR allowed detection of free radicals in complex biological specimens with high specificity and good sensitivity. In the 1950s pioneering researchers applied this technology to the study of melanin-bound radicals in biological material [8]. The development of spin traps in the late 1960s [9] allowed detection of short-lived free radical species, such as the hydroxyl and the superoxide anion radical, in biological samples.

In the early nineteenth century, oxygen was recognized as the agent causing rancidifiation of polyunsaturated natural oils Following the discovery of vitamin E in 1922 [10], it was found that vitamin E inhibited autoxidation of fats in stored food [11]. Following this there was an increasing demand for prepacked food, leading researchers to focus on the role of lipid peroxidation in food racidification. Radical chain reactions and antioxidants as radical chain-breaking agents had already attracted the interest of polymer scientists in the 1940s in their endeavor to prepare synthetic rubber and other polymers. In 1956 Harman postulated his theory on the role of free radicals in the aging process [12], and in 1958 the first studies were originated addressing cellular redox biochemistry [13]. In 1969 superoxide dismutase (SOD) was discovered as an enzyme whose role was to detoxify superoxide anion radicals [14]. At this time free radicals were considered primarily as damaging species that attack lipids, proteins, and nucleic acids, disrupting the cellular homeostasis, finally causing disease. Initially researchers focused on lipid peroxidation (see, e.g., Ref. 15), measuring free radical damage of lipids by analyzing thiobarbituric acid-reactive substances, mainly because other methods for measurement of oxidative molecular damage in biological samples were not yet available. During the late 1980s the interest in oxidative damage in biological systems shifted to studies of protein and nucleic acids oxidation. DNA is an important target of oxidative damage, since it carries the genetic information and mutations will be carried on to future generations or will fundamentally change the behavior of the cells. Reactive oxidants can generate a variety of DNA lesions, including modified bases, abasic sites, single as well as double strand breaks, DNA-protein cross-links, deletions, and duplications, and if left unrepaired such damage represent potentially mutagenic lesions.

II. FREE RADICALS AS A CAUSE OR CONSEQUENCE OF CELL DAMAGE

It was recognized early that free radicals not only cause cell injury, but may also be a consequence of cell damage [16]. Most human diseases were suggested to be accompanied by oxidative stress [17], and this concept is still valid today [1, 18]. In most cases, oxidative stress, rather than being the primary cause of disease, is a secondary complication, but in some cases it has a significant role in the pathophysiology. For instance, oxidative stress arising from exposure to environmental stressors such as irradiation or chemicals can be a major source of pathophysiological change leading to disease initiation and progression. Examples are diseases of the lung, eye, and skin where significant involvement of free radical-mediated tissue injury is indicated. Such environmental diseases comprise, e.g., UV-induced cataract, toxic dermatitis caused by oxidizing chemicals, asbestosis, silicosis, and tobacco smoke- and diesel exhaust particle-associated health problems [19]. It is clearly evident that many genetic diseases, such as thalassemias, hereditary hemochromatosis, and cystic fibrosis, are also accompanied by an imbalance in the cellular redox state (oxidative stress), which may have an influence on the disease phenotype. Research in this area is still in its infancy and mostly observational.

III. FREE RADICALS AS REGULATING SPECIES

As molecular and cell biology evolved from biochemistry, microbiology and molecular genetics in the 1980s to become a leading new discipline, an increasing interest in redox modulation of signal transduction and gene expression was developed. Several independent discoveries contributed to the evolution of this new area. For instance, nitric oxide (NO) was identified as the endothelium-derived relaxing factor in 1987 [20], and it was recognized that the free radical gas NO was a key mediator in control of vascular function. In 1998 Furchgott, Ignarro, and Murad were awarded the Nobel Prize for the discovery of NO as a signaling molecule. In the late 1980s SoxR and OxyR were identified as redox-responsive transcription regulators in Escherichia coli [21], which now serves as a model of redox-operated genetic switches [22, 23]. This was followed by the discovery of NF-κB as a redox-sensitive transcription factor in mammalian cells [24]. In the 1980s Fischer and Krebs discovered that phosphorylation and dephosphorylation reactions of proteins at tyrosine and serine/threonine mediate signal transduction from the cell surface to the nucleus; their work was awarded a Nobel Prize in 1992. It was later recognized that several kinases and phosphatases are redox sensitive (reviewed in Refs. 25, 26). These developments contributed to a paradigm shift in free radical research in biomedicine. A dualistic concept evolved postulating that reactive oxidants produced at high levels are damaging species but, when produced at low levels, they act as second messengers in numerous signal transduction pathways and gene expression systems. In contrast, the genome regulates antioxidant defense systems and their interactions and the intrinsic or constitutive level of reactive oxidants. It is now believed that redox-based regulation of signal transduction pathways and gene expression represents a fundamental cellular regulatory mechanism (see, e.g., Refs. 25–33). Table 1 presents a chronological list of important discoveries in free radical research.

Table 1 Free Radicals as Chemical and Biological Entities

IV. OXIDATIVE STRESS AND THE REDOX STATE

Oxidative stress, a term coined by Helmut Sies in the 1980s, is defined as a disturbance in the prooxidant-antioxidant balance in favor of the former [34]. Oxidative stress can result from one- or two-electron processes, and both reactions can trigger redox cascades. Although changes in the redox state and oxidative stress are closely interconnected, one- or two-electron transfer reactions may occur without any net redox change. It should be pointed out that most redox reactions in biology are two-electron processes, and oxidative stress can result from nonradical processes. According to a definition given by Schafer and Buettner, the cellular redox state is determined by the half-cell reduction potential (voltage of the relevant redox couples) and the reducing capacity (concentration of the reduced species of the relevant redox couples) of all redox-linked couples present in the compartment [35]. Since it is difficult to identify and quantitate all linked redox couples present in a compartment of interest, a representative redox couple is often used as indicator of the redox state. The redox systems PSSP/PSH (protein thiols) or PSSG/PSH (mixed thiols), NADP⁺/NADPH, GSSG/GSH (glutathione disulfide/glu...