Atorvastatin and gemfibrozil metabolites, but not the parent drugs, are potent antioxidants against lipoprotein oxidation
Introduction
Low density lipoprotein (LDL) oxidation is a key process in early atherogenesis 1, 2, 3and thus, inhibition of LDL oxidation is considered to be antiatherogenic. Very low density lipoprotein (VLDL) and high density lipoprotein (HDL) oxidation also occurs during oxidative stress 4, 5, 6, 7and may also contribute to atherogenesis. Antioxidants are derived environmentally as well as genetically. For example, dietary antioxidants, such as vitamin E [8], carotenoids 9, 10, or polyphenolic flavonoids 11, 12, associated with lipoproteins, protects them from oxidation. In addition, genetic factors, such as HDL-associated paraoxonase, also protects this lipoprotein from the damage of oxidative stress [13]. We have previously shown that the enhanced susceptibility of LDL to oxidation derived from hypercholesterolemic patients [14], is significantly reduced by hypocholesterolemic therapy 15, 16, 17, 18. Thus, hypolipidemic therapy may be considered beneficial not only because of its effects on plasma VLDL, LDL and HDL levels, but also because it can reduce the formation of atherogenic oxidized lipoproteins.
The ex vivo inhibition of LDL oxidation has been shown following the administration of the 3-hydroxy-3-methyl-glutaryl CoenzymeA (HMG-CoA) reductase inhibitors lovastatin, simvastatin, pravastatin or fluvastatin to hypercholesterolemic patients 15, 16, 17, 18, 19. The inhibitory effect of these drugs on LDL oxidizability was suggested to result from enhanced removal of plasma `aged LDL', which is more prone to oxidation than newly synthesized LDL [20]. This effect would be secondary to the statin-induced stimulation of LDL receptor activity in liver cells and to inhibition of hepatic VLDL and LDL production [21]. Metabolites of the parent statins which are produced in the liver during drug therapy may also be involved mechanistically. The hepatic P-450 drug metabolizing system actively participates in altering the parent statin structure, usually by hydroxylation 22, 23. Indeed, all the above statins, with the exception of fluvastatin, did not demonstrate direct antioxidant effects on in vitro LDL oxidation when tested at concentrations comparable to the blood drug levels observed in treated hypercholesterolemic subjects. Atorvastatin, a new inhibitor of HMG-CoA reductase, is the most effective statin for reducing both plasma total and LDL cholesterol levels. This compound also possesses significant hypotriglyceridemic properties towards all lipoprotein fractions 24, 25, 26, 27, 28. Atorvastatin therapy increases LDL receptor activity and inhibits direct production of apolipoprotein B-100 containing lipoproteins [26]. Both the parent drug and its metabolites have relatively long circulation half lives of 14–36 h 28, 29, 30. Fibrate drugs may also affect the susceptibility of lipoproteins to oxidation and we have previously shown that bezafibrate possesses [25]such a capability [17]. The fibric acid derivatives are lipid regulating drugs that promote the catabolism of triglyceride-rich lipoproteins, secondary to the activation of lipoprotein lipase [31], and the reduction of apo C-III synthesis 32, 33, 34. Another fibrate, gemfibrozil has been shown to not only reduce plasma triglycerides [35]but also to increase plasma HDL concentration in humans 36, 37, and to reduce plasma lipoprotein(a) levels in male cynomolgus monkeys [38]. In humans, gemfibrozil is metabolized to gemfibrozil acyl glucoronides 39, 40, and these metabolites are found in the plasma and urine of volunteers following treatment. The level of the p-hydroxy metabolite of gemfibrozil (metabolite I) found in the plasma of gemfibrozil treated rodents is much higher than that of treated humans and most likely reflect differences in dose and metabolism. The present study was undertaken in order to elucidate the effects of atorvastatin and gemfibrozil, as well as specific hydroxylated metabolites (alone and in combination) on LDL, VLDL and HDL susceptibility to oxidation. Our results clearly demonstrate the inhibitory effects of the drug metabolites (but not of the parent drugs) on plasma lipoprotein oxidation individually, and an additive effect, when combined. These observations suggest that the metabolites may prevent lipoproteins oxidation and thereby reduce their atherogenic potential.
Section snippets
Materials
Atorvastatin and its o-hydroxy and p-hydroxy metabolites, as well as gemfibrozil and its metabolite I were synthesized at Parke Davis Pharmacuticals Research, (Warner-Lambert, Ann Arbor, MI). The p-. metabolite of atorvastatin: [3R,5R]-2-fluoro-phenyl-β-δ-dihydroxy-5-(1-isopropyl)-3-phenyl-4-[(4-hydroxy-phenyl-amino)-carbonyl]-1H-pyrrole-1-heptanoic acid, calcium salt, hydrate. The o-hydroxy metabolite of atorvastatin: [3R,5R]-2-fluoro-phenyl-β-δ
Results
The effect of atorvastatin and its metabolites, as well as that of gemfibrozil and its metabolite, on the susceptibility of lipoproteins to oxidation was studied in several oxidation systems including those containing metal ions (10 μM CuSO4) those having the capacity to generate free radicals (5 mM AAPH), and those that mimic biological oxidation (J-774A.1 macrophage-like cell line).
Discussion
The present study demonstrated that metabolites of a new HMG-CoA reductase inhibitor, atorvastatin [22], and of the fibric acid derivative, gemfibrozil significantly inhibited lipoprotein oxidation in several oxidation systems. LDL oxidation is considered to be a key event in atherogenesis as it contributes to macrophage cholesterol accumulation and foam cell formation, as well as to cytotoxicity, thrombosis and inflammation 1, 2, 3, 49, 50. Hence, inhibition of LDL oxidation may contribute to
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