Effect of Gemfibrozil on HDL-Associated Serum Paraoxonase Activity and Lipoprotein Profile in Patients with Hyperlipidaemia
Tóm tắt
Objective: Earlier studies pointed out that the high density lipoprotein (HDL)-associated paraoxonase (PON) activity was decreased in patients with hyperlipidaemia compared with healthy age-matched controls. PON can inhibit low density lipoprotein (LDL) oxidation and has an antiatherogenic effect. The aim of the present study was to evaluate the effect of gemfibrozil on serum PON and lipoprotein levels in patients with hyperlipidaemia.
Patients and Methods: 57 patients with hypertriglyceridaemia were enrolled in the study (26 males, 31 females). The mean (± SD) body mass index was 26.17 ±6.17 kg/m2. The effects of twice daily gemfibrozil 600mg on serum cholesterol, lipoproteins, triglyceride, apolipoproteins and fibrinogen levels as well as on liver and kidney function were measured. Serum PON activity was determined spectrophotometrically using paraoxon as substrate.
Results: Following treatment with gemfibrozil for 3 months, serum triglyceride and cholesterol levels were significantly decreased (from 4.01 ± 1.95 to 2.69 ± 1.61 mmol/L; p < 0.003 and from 7.44 ± 2.45 to 6.22 ± 0.96 mmol/L; p < 0.05, respectively), while the protective HDL level was not significantly increased. Furthermore, the low density lipoprotein (LDL) level was not significantly decreased while the apolipoprotein B-100 level was significantly reduced (from 1.36 ± 0.29 to 1.28 ± 0.22 g/L; p < 0.05), and apolipoprotein A1 remained unchanged. The serum PON activity was significantly increased (from 220 ± 98 to 253 ± 100 U/L; p < 0.001). Standardised values for HDL (PON/HDL) were also significantly increased (from 190 ± 85 to 235 ± 104; p < 0.01).
Conclusions: Gemfibrozil has a lipid-lowering effect in hypertriglyceridaemic patients and may improve the antioxidant status by increasing serum PON activity.
Tài liệu tham khảo
Pyörälä K, Laakso M, Uusitupa M. Diabetes and atherosclerosis: an epidemiological view. Diab Metab Rev 1987; 3: 463–524
Krolewski AS, Warram JH, Valsania P, et al. Evolving natural history of coronary artery disease in diabetes mellitus. Am J Med 1991; 90Suppl. 2A: 56S–61S
Parthasarathy S, Printz DJ, Boyd D, et al. Macrophage oxidation of low density lipoprotein generates a modified from recognized by the scavenger receptor. Atherosclerosis 1986; 6: 505–10
Henriksen T, Mahoney EM, Steinberg D. Enhanced macrophage degradation of biologically modified low density lipoprotein. Atherosclerosis. 1983; 3: 149–59
Brown MS, Goldstein JL. Scavenging for receptors. Nature 1990; 343: 508–9
Cushing SD, Berliner JA, Valente AT, et al. Minimally modified low density lipoprotein induces monoyte chemotactic protein 1 in human endothelial cells and smooth muscle cells. Proc Natl Acad Sci USA 1990; 87: 5134–8
Navab M, Imes SS, Hough GP, et al. Monocyte transmigration induced by modofication of low density lipoprotein in cocultures of human aortic wall cells is due to induction of monocyte chemotactic protein I synthesis and is abolished by high density lipoprotein. J Clin Invest 1991; 88: 2039–46
Berliner JA, Territo MC, Sevanian A, et al. Minimally modified low density lipoprotein stimulates monocyte endothelial interactions. J Clin Invest 1990; 85: 1260–6
Hessler JR, Robertson Jr AL, Chisolm GM. LDL-induced cytotoxicity and its inhibition by HDL in human vascular smooth muscle and endothelial cells in culture. Atherosclerosis 1979; 32: 213–29
Parthasarathy S, Barnett J, Fong LG. High density lipoprotein inhibits the oxidative modification of low density lipoprotein. Biochim Biophys Acta 1990; 1044: 275–83
Maier JAM, Barenghi L, Pagani F, et al. The protective role of high-density lipoprotein on oxidized-low-density-lipoprotein-induced U937 / endothelial cell interactions. Eur J Biochem 1994; 221: 35–41
La Du BN. Human serum paraoxonase/arylesterase. In: Kalow W, editor. Pharmacogenetics of drug metabolism. New York: Pergamon Press, Inc., 1992: 51–91
Mackness MI, Arrol S, Durrington PN. Paraoxonase prevents accumulation of lipoperoxides in low density lipoprotein. FEBS Lett 1991; 286: 152–4
Watson AD, Berliner JA, Hama SY, et al. Protective effect of high density lipoprotein associated paraoxonase. Inhibition of the biological activity of minimally oxidized low density lipoprotein. J Clin Invest 1995; 96: 2882–91
Mackness MI, Arrol S, Abbott CA, et al. Is paraoxonase related to atherosclerosis. Chem Biol Interac 1993; 87: 161–71
Paragh Gy, Seres I, Balogh Z, et al. The serum paraoxonase activity in patients with chronic renal failure and hyperlipidemia. Nephron 1998; 80: 166–70
Paragh Gy, Asztalos L, Seres I, et al. Serum paraoxonase activity changes in uremic and kidney transplanted patients. Nephron 1999; 83: 126–31
Saha N, Roy AC, Teo SH, et al.Influence of serum paraoxonase polymorphism on serum lipids and apolipoproteins. Clin Genet 1991; 40(4): 277–82
Auwerx J, Schoonjans K, Fruchart JC, et al. Transcriptional control of triglyceride metabolism: fibrates and fatty acids change the expression of the LPL and apo C-III genes by activating the nuclear receptor PPAR. Atherosclerosis 1996; 124 Suppl.: S29–37
Clauss A. Gerinnungsphysiologische schnellmerhode zur bestimmung des fibrinogenes. Acta Haematol 1957; 17: 237–46
Abbott CA, Mackness MI, Kumar S, et al. Serum paraoxonase activity, concentration, and phenotype distribution in diabetes mellitus and its relationship to serum lipids and lipoproteins. Arterioscler Thromb Vase Biol 1995
Castelli WP. The triglyceride issue: a view from Framingham. Am Heart J 1986; 112: 432–7
Baingon D, Miller NE, Bolton CH, et al. Plasma triglyceride and high density lipoprotein cholesterol as predictors of ischaemic heart disease in British men. The Caerphilly and Speedwell Collaborative Heart Disease Studies. Br Heart J 1992; 68: 60–6
Assmann G, Schulte H. Relation of high density lipoprotein cholesterol and triglycerides to atherosclerotic coronary artery disease (the PROCAM experience). Am J Cardiol 1992; 70: 733–7
Manninen V, Tenkanen L, Koskinen P, et al. Joint effects of serum triglyceride and LDL cholesterol and HDL cholesterol concentrations on coronary heart disease risk in the Helsinki Heart Study. Implications fortreatment. Circulation 1992; 70: 733–7
Huttunen JK, Manninen V, Manttari M, et al. The Helsinki Heart Study: central findings and clinical implications. Ann Med 1991; 23: 155–9
Hokanson JE, Austin MA. Plasma triglyceride level is a risk factor for cardiovascular disease independent of high-density lipoprotein cholesterol level: a metaanalysis of population-based prospective studies. J Cardiovasc Risk 1996; 3: 213–9
Austin MA, Brunzell JD, Fitch WL, et al. Inheritance of low density lipoprotein subclass patterns in familial combined hyperlipidemia. Arteriosclerosis 1990; 10: 520–30
Wilhelmsen K, Svardsudd K, Korsan-Bengtsen K, et al. Fibrinogen as a risk factor for stroke and myocardial infarction. N Engl J Med 1984; 311: 501–5
Bruckert E, Gheron G, Dairou F. Comparisons de l’efficacite et de la tolerance du ciprofibrate et du gemfibrozil dans le traitement des hyperlipidemies de Type lla et de Type II. Synthese Med 1988; 429: 14–6
Branchi A, Rovellini A, Sommariva D, et al. Effect of three fibrate derivates and two HMG-CoA reductase inhibitors on plasma fibrinogen level in patients with primary hypercholesterolemia. Thromb Haemost 1993; 70: 241–3
Niort G, Bulgarelli A, Cassader M, et al. Effect of short-term treatment with bezafibrate on plasma fibrinogen, fibrino-peptide A, platelet activation and blood filterability in atherosclerotic hyperfibrinogenemic patients. Atherosclerosis 1988; 71: 113–9
Homma Y, Ozawa H, Kobayashi T, et al. Effects of bezafibrate therapy on subfractions of plasma low-density of lecithin: cholesterol acyltransferase and cholesteryl ester transfer protein in patients with hyperlipoproteinemia. Atherosclerosis 1994; 106: 191–201
Sommariva D, Tirrito M, Bonfiglioli D, et al. Long-term effects of bezafibrate and of a bezafibrate and cholestyramine combination on lipids and lipoprotein lipids in type IIa hypercholesterolaemic patients. Int J Clin Pharmacol Res 1986; 6: 249–53