Lipid peroxidation (LPO) is a free radical-related process that in biologic systems may occur under enzymatic control, e.g., for the generation of lipid-derived inflammatory mediators, or nonenzymatically. This latter form is associated mostly with cellular damage as a result of oxidative stress, which also involves cellular antioxidants in this process. This article focuses on the relevance of two LPO products, malondialdehyde (MDA) and 4-hydroxynonenal (HNE), to the pathophysiology of human disease. The former has been studied in human serum samples of hepatitis C virus-infected adults and human immunodeficiency virus-infected children. In these two cases it is shown that the specific assay of serum MDA is useful for the clinical management of these patients. The presence of MDA in subretinal fluid of patients with retinal detachment suggests the involvement of oxidative stress in this process. Moreover, we were able to report the dependence of this involvement on the degree of myopia in these patients. The assay of MDA contents in the peripheral nerves of rats fed a chronic alcohol-containing diet or diabetic mice also confirms the pathophysiologic role of oxidative stress in these experimental models. In these two cases, associated with an increase in tissue LPO products content, we detected a decrease of glutathione peroxidase (GSHPx) activity in peripheral nerve, among other modifications. We have demonstrated that in vitro HNE is able to inhibit GSHPx activity in an apparent competitive manner, and that glutathione may partially protect and/or prevent this inactivation. The accumulation of LPO products in the brain of patients with Alzheimer's disease has also been described, and it is on the basis of this observation that we have tried to elucidate the role of oxidative stress and cellular antioxidants in beta-amyloid-induced apoptotic cell death of rat embryo neurons. Finally, we discuss the possible role of the observed vascular effects of HNE on human arteries. -- Environ Health Perspect 106(Suppl 5):1229-1234 (1998).
Key words: hepatitis C, human immunodeficiency virus, interferon alpha2, lipid peroxidation, oxidative stress, retinal detachment, antioxidants, malondialdehyde, 4-hydroxynonenal, glutathione, glutathione peroxidase, beta-amyloid, Alzheimer's disease
Inflammation associated with infectious and degenerative diseases, and probably others, leads to the activation of the so-called inflammatory cells. This activation by means of several mechanisms involving neutrophils, endothelial cells, etc., might promote oxidative stress. Oxidative stress was originally defined as the disequilibrium between prooxidants and antioxidants in biological systems (
To demonstrate involvement of oxidative stress as pathophysiologic mechanisms in diseases or experimental models, several approaches are possible. Because oxidative stress may lead to cellular damage, any marker of cellular disruption may confirm this role, although it may still be necessary to demonstrate directly the intervention of oxidative stress. This may be achieved by the direct detection of activated species in situ, the assay of end products of protein or lipid oxidation, or any other oxidative modification of macromolecules (modified bases of nucleotides, etc.). Further evidence for the role of oxidative stress may be obtained by studying the content and activity of antioxidants. In this review, our data attempt to demonstrate the crucial role of oxidative stress in different disease and experimental models. The goal is different for each model. In some, the detection of end products of LPO may help the clinical management of these patients; in others, oxidative stress participation is reported for the first time. Finally other results may help to understand pathophysiologic mechanisms that are observed in these diseases or experimental models.
We have studied serum MDA concentrations in two relevant viral infections that have in common the involvement of T cells: hepatitis C virus (HCV) in adults (
We have also demonstrated the pathophysiologic role of oxidative stress in experimental diabetic neuropathy (
It has been reported that serum LPO products are increased in patients with liver disease also in chronic hepatitis C (CHC) patients (
The existence of an agent causing non-A, non-B hepatitis was documented by Alter et al. (
We reported that serum LPO products were significantly increased in a selected group of patients with CHC before interferon (IF) alpha-2 treatment (
These results confirm involvement of oxidative stress as part of the pathophysiology of CHC. The increase in serum MDA concentration in CHC patients may fit in well with the recently reported GSH depletion observed in hepatic tissue, plasma, and peripheral blood mononuclear cells of CHC patients (
Factors that correlate with the outcome of the human immunodeficiency virus (HIV) infection are needed for a better understanding of the pathogenesis of this infection and certainly for a better clinical management of the infected individuals. This is of special relevance in particularly important for HIV seropositive children. HIV infection is associated with oxidative stress., in view, among other things, of the reduction of glutathione GSH contents in plasma and lung epithelial lining fluid (
The HIV infection in children has some special features. Infants of HIV seropositive mothers are almost always seropositive at birth but might during the first 18 months of life turn seronegative if they are not infected (
LPO products and proteins accumulate in the subretinal fluid of patients undergoing retinal detachment surgery (
This same approach, i.e., the evaluation of tissue LPO products levels in tissues, has been also applied to experimental models with similar results. We have focused in the last few years on the role of oxidative stress in peripheral nervous tissue affections, i.e., neuropathies. This has been reviewed elsewhere (
The alterations observed in GSHPx activity might be related to different mechanisms. However, the reported ability of HNE to modify proteins and therefore influence enzymatic activity, led us to study the possibility of a direct interaction between HNE and GSHPx. HNE reacts with GSH spontaneously, but within cells this reaction proceeds at a much higher rate, catalyzed by specific isoforms of GSH S-transferases (
Incubation of GSHPx with HNE resulted in a loss of enzymatic activity, in a time-and concentration-dependent fashion. Over 90% of the inhibition observed for each of the different concentrations was achieved in the first 30 min, and no further loss of activity could be detected. We calculated the concentration that exerted 50% inactivation of the enzyme (I
Oxygen radicals and lipid peroxidation play a pivotal role in the observed damage during central nervous system trauma and stroke (
As mentioned above, HNE is able to impair Na,K-ATPase activity (
LPO products such as lipid hydroperoxides (
This paper is based on a presentation at the Second international Meeting on Oxygen/Nitrogen Radicals and Cellular Injury held 7-10 September 1997 in Durham, North Carolina. Manuscript received at EHP 19 December 1997; accepted 16 June 1998.
This work was partially supported by grants 96/1504 from Fondo de Investigaciones Sanitarias (Spain) and PM96-0103 from Direccion General de Ensenanza (Spain) to F JR.
Abbreviations used: AD, Alzheimer's disease; ALT, alanine aminotransferase; CDC, Centers for Disease Control and Prevention; CHC, chronic hepatitis C; GSH, glutathione; GSHPx, glutathione peroxidase; HCV, hepatitis C virus; HIV, human immunodeficiency virus; HNE, 4-hydroxynonenal; IF, interferon alpha-2b; LPO, lipid peroxidation; MDA, malondialdehyde; TBA, thiobarbituric acid; TBARS, thiobarbituric acid reactive substances.
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By Francisco J. Romero; Francisco Bosch-Morell; Maria J. Romero; Enrique J. Jareno; Belen Romero; Nuria Marin and Joaquin Roma
Department of Physiology, School of Medicine and Dentistry, University of Valencia, Valencia, Spai
Address correspondence to F.J. Romero, Experimental Toxicology and Neurotoxicology Unit, Department of Physiology, School of Medicine and Dentistry, University of Valencia, Avienda. Blasco Ibanez, 17, 46010-Valencia, Spain. Telephone: 34 6 386 4646. Fax: 34 6 386 4642 E-mail: fco.romero@uv.es