Assessment of paraoxonase 1 activity and malondialdehyde levels in patients with rheumatoid arthritis
Introduction
Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by persistent synovitis involving peripheral joints in a symmetrical distribution. Typical pathological findings in RA are the degradation of articular cartilage and bone destruction. The rheumatoid synovium is characterized by hyperplasia of synovial lining cells, alteration in capillary vessels, edema and infiltration with mononuclear cells, which are often located around small blood vessels [1].
The cause of RA remains unknown. Present data suggest that reactive oxygen species (ROS) play an important role in the pathogenesis of RA [2]. ROS are highly reactive molecules that, when present in excess, overwhelm the protective systems and results in cell damage and lipid peroxidation [3], [4]. ROS are formed in oxidative processes that normally occur at relatively low levels in all cells and tissues. Under normal conditions, a variety of antioxidant mechanisms serve to control this production. In contrast, high doses and/or inadequate removal of ROS result in oxidative stress, which may cause severe metabolic malfunctions and damage to biological macromolecules. Further, decomposition of peroxidized lipid yields a wide variety of end-products, including malondialdehyde (MDA) [5].
Lipid peroxidation is a well-established mechanism of cellular injury in humans, and is used as an indicator of oxidative stress in cells and tissues. Lipid peroxides, derived from polyunsaturated fatty acids, are unstable and decompose to form a complex series of compounds. These include reactive carbonyl compounds, which are the most abundant MDA. Therefore, measurement of MDA is widely used as an indicator of lipid peroxidation. Increased levels of lipid peroxidation products have been associated with a variety of diseases in both humans and model systems [6], [7].
Blood paraoxonase (PON1) is a calcium-dependent esterase that is known to catalyze hydrolysis of organophosphates, and is widely distributed among tissues such as liver, kidney, intestine and also plasma [8], [9]. PON1, which is exclusively bound to high-density lipoprotein (HDL), is recognized as an antioxidant enzyme because it hydrolyses lipid peroxides in oxidized lipoproteins [10], [11]. PON1 activity was suggested to be inversely associated with oxidative stress in serum and macrophages [12]. Reduced PON1 activities have been reported in several groups of patients with diabetes, hypercholesterolemia and cardiovascular disease who are under increased oxidative stress [13], [14].
Cardiovascular disease is the first cause of death in RA patients, with the incidence of this disease being higher than in the control population [15], [16]. LDL oxidation in arterial walls is believed to have an important role in atherogenesis [17], [18]. Therefore, mechanisms that prevent the oxidation of LDL have received increasing attention in recent years. One such mechanism is the prevention of LDL oxidation by PON1. It has been shown that PON1 lowers the sensitivity of LDL to lipid peroxidation. This finding supports the theory that PON1 may have a potential role in the detoxification of lipid peroxides [19].
MDA has not been searched for together with the antioxidant enzyme PON1 in RA patients so far. In the present study, we aimed to determine serum PON1 activities as known lipid antioxidant and MDA levels, end products of lipid peroxidation, induced by ROS for evaluating oxidative stress in RA patients.
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Patients
Fifty-seven patients with RA were included in the study. Mean (±SD) age was 46.01 ± 7.59 years and the mean (±SD) duration of the disease was 101.89 ± 65.87 months. The patients fulfilled the 1987 revised American College of Rheumatology criteria for RA [20]. Differentiation between the “active and “inactive” groups was made according to the ACR preliminary criteria for complete clinical remission of RA, as suggested by Pinals et al. [21]. Briefly, six criteria yielded optimal discrimination:
Assay of paraoxonase activity
Serum PON1 activity was measured according to a method described elsewhere [22]. We measured the rate of hydrolysis of paraoxon by monitoring the increase of absorbance at 405 nm and at 25°C. The basal assay mixture included 1.0 mM paraoxon and 1.0 mM CaCl2 in 0.05 M glycine buffer, pH 10.5. One unit (IU) of paraoxonase activity is defined as 1 μmol of p-nitrophenol formed per minute, and activity was expressed as U/L of serum.
Measurement of serum MDA concentration
Serum MDA levels were measured according to a method described
Results
There was not a statistically significant difference of age and sex distribution between the control and RA groups (P > 0.05).
Serum MDA level was higher in the patient group than the controls (P = 0.001) but PON1 activity was found to be lower (P = 0.001) in the patient group than the control group. PON1 activity and MDA levels are presented in Table 1. CV's of the methods were 3.6 for the MDA levels and 3.5 for the PON1 activity. When active and inactive subgroups were compared with the
Discussion
ROS molecules are highly reactive and can attack almost every cell component, causing further damage to the surrounding tissues. ROS overwhelm the protective systems and result in cell damage and lipid peroxidation, which play a crucial and possibly causative role in the pathogenesis of a number of acute and chronic diseases, such as inflammation, cancer, liver injury, atherosclerosis and rheumatoid arthritis [3], [4]. Several reports have suggested that the increased ROS production in patients
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