INFLUENCE OF PROBUCOL ON ENHANCED LDL OXIDATION AFTER FISH-OIL TREATMENT OF HYPERTRIGLYCERIDEMIC PATIENTS

The susceptibility of low-density lipoprotein (LDL) to oxidation was studied in hypertriglyceridemic men (5 with type III and 5 with type IV) at baseline on a low-saturated-fat, low-cholesterol diet, after 6 weeks of dietary supplementation with fish oil (Promega, 12 g/d), and after 6 weeks of fish oil combined with probucol (500 mg BID). The relative content of n-3 polyunsaturated fatty acids in plasma and LDL was increased during the two treatment periods, and a low alpha-tocopherol to n-3 polyunsaturated fatty acids ratio was observed. Plasma thiobarbituric acid-reactive substances (TBARS) levels were unchanged after 6 weeks of fish oil, but the ratio of lipid peroxides to the reduced triglyceride (TG) levels (MDA:TG) was significantly higher (P<.01). Addition of probucol lowered both absolute levels of TBARS (P<.01) and the MDA to TG ratio (P<.001). The susceptibility of LDL to Cu2+-catalyzed oxidation was evaluated over a 5-hour time course by determining TBARS formation, free amino group levels, and changes in LDL electrophoretic mobility. TBARS levels that were higher in native LDL (1.019<d<1.050 g/mL) after 6 weeks of fish oil than at baseline (P<.01) were reduced 52.3+/-11.3% by the addition of probucol (P<.001). With fish oil alone, TBARS production after exposure of LDL to Cu2+ for 5 hours was increased 17.0+/-5.8% compared with corresponding baseline values (P<.001), whereas a 64.1+/-14.3% reduction from the previous period was observed with fish oil+probucol (P<.001). Determination of LDL reactive amino groups further documented the structural changes occurring with peroxide formation, which were opposed by probucol. Our observations emphasize a potential risk associated with intake of large doses of fish oil in the treatment of hyperlipidemia and further demonstrate the ability of probucol as an antioxidant.