Oxidative Stress & Antioxidants and PON1 in Health and Disease (original) (raw)

2008, The Paraoxonases: Their …

Impairment in oxidative stress/antioxidant balance is an important trigger for a variety of diseases. As an antioxidant molecule on HDL, paraoxonase (PON) contributes to the antioxidant mechanisms by removing oxidised lipids both on HDL and LDL. In this chapter, we will document and evaluate the results of our studies on healthy, atheroscleoric and diabetic cases which showed that (a) PON, superoxide dismutase (SOD) and arylesterase probably work in a collaboration against oxidative stress, especially superoxide radical scavenging; (b) PON and SOD activities concomitantly decrease with the oxidative stress & severity of disease (higher HbA1c values in diabetics, more diseased vessels in atherosclerosis) while catalase (CAT) acts the opposite way; (c) depletion of PON activity may be mainly attributed to oxidative inactivation by lipid hydroperoxides; (d) Since PON1 activity and eTBARS levels are affected by traditional risk factors (hypertension, aging and gender), determination of arylesterase activity might be a better indicator of antioxidant activity of PON1; (e) SOD activity has the greatest variability in EY SOZMEN ET AL regard to PON phenotype therefore it's important to define the PON1 polymorphism as well as PON, arylesterase and other antioxidant enzyme activities. Enhancement of free radicals and impairment of antioxidant status are crucial processes underlying pathophysiologic mechanisms in a variety of diseases including atherosclerosis, diabetes mellitus and cancer (Mates JM, Parthasarathy S, Aguirre F). Enzymatic and nonenzymatic antioxidant systems (such as superoxide dismutase-SOD, catalase-CAT, glutathione peroxidase-GPx, paraoxonase-PON and vitamin E) are important in scavenging free radicals and their metabolic products as well as in maintaining normal cellular physiology, promotion of immunity and prevention of various diseases (Mates JM). Experimental, clinical and epidemiological studies have shown the depletion of various antioxidants in a variety of diseases (Mates JM, Parthasarathy S, Aguirre F, Maxwell SRJ). In this review, we focused on oxidative stress and antioxidant systems both in healthy humans and in patients with atherosclerosis and diabetes, emphasizing the changes in oxidant/antioxidant status in regard to PON phenotyping as well as PON genotyping in order to elucidate the antioxidant role of PON. Relationship between PON and other antioxidant enzymes in healthy humans and in diseases According to the "oxidative modification hypothesis", atherogenesis is initiated by oxidation of the low-density lipoprotein (LDL) (Ross R, Aviram M 1996, Steinberg D, Chisolm GM) and increasing evidence suggests that this modification plays a central role in the further propagation of atherogenesis as well (Jialal I, Chisolm GM, Kaplan M, Steinberg D, Parthasarathy S). The LDL oxidative state is elevated by increased ratio of poly/mono unsaturated fatty acids in LDL and it is reduced by enhanced LDL-associated antioxidant content such as vitamin E, beta-carotene, EY SOZMEN ET AL lycopene, polyphenolic flavonoids and other external antioxidants (Aviram M 2005). Recently it has been shown that PON1 prevents LDL from oxidation by removing oxidised phosholipids from LDL. This is supported by the finding in PON1-knock out mice in which PON's preventive effect on LDL oxidation was not observed (Mackness MI 1996, Laplaud RM, Durrington PN, Shih DM). Apart from PON, other antioxidant systems are important in the prevention of various diseases by scavenging free radicals (Mates JM). Previous research on PON and antioxidants (such as SOD, CAT, GPx, etc.) triggered our work on the role of antioxidant enzymes in the maintenance of PON activity during LDL oxidation in various groups namely, healthy, diabetic and atherosclerotic cases. Our first study indicated a negative correlation between PON activities and conjugated diene (r= -0.297, p=0.034) & TBARS (r= -0.265, p=0.053) levels of LDL at baseline (Sozmen EY, 2001b). Another important finding of our study was the positive correlation between SOD and PON activity in healthy cases (n=66) (Figure-1).