A new compound-specific pleiotropic effect of statins: modification of plasma gamma-tocopherol levels.
Gamma tocopherol (gamma-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 gamma-T metabolism. Patients with ATP III criteria for statin use (n=35) were randomly allocated to treatment with simvastatin 20mg/day or pravastatin 40 mg/day. Plasma lipids, alpha-tocopherol (alpha-T), gamma-T as well as the urinary excretion of the gamma-T metabolite 2,7,8-trimethyl-2-(2'carboxyethyl)-6-hydroxychroman (gamma-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 alpha-T levels (-17.5+/-4.2 and -12.2+/-4.1%), and increased the alpha-T/LDL-C ratios (51.4+/-14.6 and 60.4+/-15%). Conversely, pravastatin did not affect whereas simvastatin significantly augmented plasma gamma-T levels (22+/-7.9%, p=0.009, between groups p=0.0045). Moreover, the gamma-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 gamma-CEHC (34.3+/-17.3%, p=0.056; between groups p=0.046). In conclusion, simvastatin and pravastatin produced distinct effects on gamma-T metabolism, presumably as a result of different statin-CYP interactions.
Werba
José P
JP
Centro Cardiologico Monzino IRCCS, Via Parea, 4, 20138 Milan, Italy. pablo.werba@ccfm.it
Cavalca
Viviana
V
Veglia
Fabrizio
F
Massironi
Paola
P
De Franceschi
Michela
M
Zingaro
Lorenzo
L
Tremoli
Elena
E
D000328:Adult; D000368:Aged; D008078:Cholesterol, LDL / Q000097:blood; D002839:Chromans / Q000652:urine; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008055:Lipids / Q000097:blood; D008297:Male; D008875:Middle Aged; D017035:Pravastatin / Q000494:pharmacology; D011422:Propionates / Q000652:urine; D011446:Prospective Studies; D019821:Simvastatin / Q000494:pharmacology; D024504:gamma-Tocopherol / Q000097:blood*
D008078:Cholesterol, LDL; D002839:Chromans; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008055:Lipids; D011422:Propionates; C107690:2,7,8-trimethyl-2-(beta-carboxyethyl)-6-hydroxychroman; D024504:gamma-Tocopherol; D019821:Simvastatin; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D017035:Pravastatin