REDUCED SUSCEPTIBILITY OF LOW-DENSITY-LIPOPROTEIN (LDL) TO LIPID-PEROXIDATION AFTER FLUVASTATIN THERAPY IS ASSOCIATED WITH THE HYPOCHOLESTEROLEMIC EFFECT OF THE DRUG AND ITS BINDING TO THE LDL

Increased plasma cholesterol concentration in hypercholesterolemic pat ients is a major risk factor for atherosclerosis. The impaired removal of plasma low density lipoprotein (LDL) in these patients results in the presence of their LDL in the plasma for a long period of time and thus can contribute to its enhanced oxidative modification. In the pre sent study we analyzed the effect of the hypocholesterolemic drug, flu vastatin, on plasma and LDL susceptibilities to oxidation during 24 we eks of therapy. Fluvastatin therapy (40 mg/day for 24 weeks) in 10 hyp ercholesterolemic patients resulted in 30%, 34% and 22% decrements in plasma levels of total cholesterol, LDL cholesterol and triglycerides, respectively. This effect has been achieved after only 4 weeks of the rapy. We next studied the effect of fluvastatin therapy on LDL suscept ibility to oxidation in vivo and in vitro. 2.2-Azobis, 2-amidinopropan e hydrochloride (AAPH, 100 mM)-induced plasma lipid peroxidation was d ecreased by 70% and 77% after 12 weeks and 24 weeks of fluvastatin the rapy respectively. The lag time required for the initiation of CuSO4 ( 10 mu M)-induced LDL oxidation was prolonged by 1.2- and 2.5-fold, aft er 12 and 24 weeks of fluvastatin therapy respectively. We next analyz ed the in vitro effect of fluvastatin on plasma and LDL susceptibiliti es to oxidation. Preincubation of plasma or LDLs that were obtained fr om normal subjects with 0.1 mu g/ml of fluvastatin, caused 20% or 57% reduction in AAPH-induced lipid peroxidation, respectively. Similarly, a 1.6- and 2.7-fold prolongation of the lag time required for CuSO4-i nduced LDL oxidation was found following LDL incubation with 0.1 and 1 .0 mu g/ml of fluvastatin, respectively. To find out possible mechanis ms that contribute to this inhibitory effect of fluvastatin on LDL oxi dizability, we analyzed the antioxidative properties of fluvastatin. F luvastatin did not scavenge free radicals and did not inhibit linoleic acid peroxidation. Fluvastatin also did not act as a chelator of copp er ions. However, fluvastatin was shown to specifically bind mainly to the LDL surface phospholipids and this interaction altered the lipopr otein charge as evident from the 38% decrement in the electrophoretic mobility of fluvastatin-treated LDL, in comparison to nontreated LDL. The inhibitory effect of fluvastatin therapy on LDL oxidation probably involves both its stimulatory effect on LDL removal from the circulat ion, as well as a direct binding effect of the drug to the lipoprotein . We thus conclude that the antiatherogenic properties of fluvastatin may not be limited to its hypocholesterolemic effect, but could also b e related to its ability to reduce LDL oxidizability. Copyright (C) 19 97 Elsevier Science Ireland Ltd.