A new compound-specific pleiotropic effect of statins: Modification of plasma gamma-tocopherol levels

Gamma tocopherol (γ-T) is a recognized peroxynitrite scavenger, reputedly metabolized via the cytochrome P450 3A4 (CYP3A4). In this study, we assessed whether equipotent LDL-lowering doses of statins with or without inhibitory activity on CYP3A4 differently affect γ-T metabolism. Patients with ATP III criteria for statin use (n = 35) were randomly allocated to treatment with simvastatin 20 mg/day or pravastatin 40 mg/day. Plasma lipids, α-tocopherol (α-T), γ-T as well as the urinary excretion of the γ-T metabolite 2,7,8-trimethyl-2-(2′carboxyethyl)-6-hydroxychroman (γ-CEHC), were determined at baseline and after 6 weeks of treatment. Pravastatin and simvastatin equally reduced LDL-C (-42.8 ± 2.9 and -42.1 ± 3.0%) and α-T levels (-17.5 ± 4.2 and -12.2 ± 4.1%), and increased the α-T/LDL-C ratios (51.4 ± 14.6 and 60.4 ± 15%). Conversely, pravastatin did not affect whereas simvastatin significantly augmented plasma γ-T levels (22 ± 7.9%, p = 0.009, between groups p = 0.0045). Moreover, the γ-T/LDL-C ratio increased significantly more with simvastatin than with pravastatin (124 ± 23 versus 61.3 ± 22.1%, p = 0.05 between groups). In addition, pravastatin but not simvastatin increased the urinary excretion of γ-CEHC (34.3 ± 17.3%, p = 0.056; between groups p = 0.046). In conclusion, simvastatin and pravastatin produced distinct effects on γ-T metabolism, presumably as a result of different statin-CYP interactions.