ATORVASTATIN AND GEMFIBROZIL METABOLITES, BUT NOT THE PARENT DRUGS, ARE POTENT ANTIOXIDANTS AGAINST LIPOPROTEIN OXIDATION

Citation
M. Aviram et al., ATORVASTATIN AND GEMFIBROZIL METABOLITES, BUT NOT THE PARENT DRUGS, ARE POTENT ANTIOXIDANTS AGAINST LIPOPROTEIN OXIDATION, Atherosclerosis (Amsterdam), 138(2), 1998, pp. 271-280
Citations number
54
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Peripheal Vascular Diseas
Journal title
ISSN journal
0021-9150
Volume
138
Issue
2
Year of publication
1998
Pages
271 - 280
Database
ISI
SICI code
0021-9150(1998)138:2<271:AAGMBN>2.0.ZU;2-9
Abstract
Increased atherosclerosis risk in hyperlipidemic patients may be a res ult of the enhanced oxidizability of their plasma lipoproteins. We hav e previously shown that hypocholesterolemic drug therapy, including th e 3-hydroxy-3-methyl-glutaryl CoenzymeA (HMG-CoA) reductase inhibitors , and the hypotriglyceridemic drug bezafibrate, significantly reduced the enhanced susceptibility to oxidation of low density lipoprotein (L DL) isolated from hyperlipidemic patients. Although this antioxidative effect could not be obtained in vitro with all of these drugs, the ac tive drug metabolites, which are formed in vivo, could affect lipoprot ein oxidizability. We thus sought to analyze the effect of atorvastati n and gemfibrozil, as well as specific hydroxylated metabolites, on th e susceptibility of LDL, very low density lipoprotein (VLDL), and high density lipoprotein (HDL) to oxidation. LDL oxidation induced by eith er copper ions (10 mu M CuSO4), by the free radical generator system 2 '-2'-azobis 2-amidino propane hydrochloride (5 mM AAPH), or by the J-7 74A.1 macrophage-like cell line, was not inhibited by the parent forms of atorvastatin or gemfibrozil, but was substantially inhibited (57-9 7%), in a concentration-dependent manner, by pharmacological concentra tions of the o-hydroxy and the p-hydroxy metabolites of atorvastatin, as well as by the p-hydroxy metabolite (metabolite I) of gemfibrozil. On using the atorvastatin o-hydroxy metabolite and gemfibrozil metabol ite I in combination an additive inhibitory effect on LDL oxidizabilit y was found. Similar inhibitory effects (37-96%) of the above metaboli tes were obtained for the susceptibility of VLDL and HDL to oxidation in the oxidation systems outlined above. The inhibitory effects of the se metabolites on LDL, VLDL, and HDL oxidation could be related to the ir free radical scavenging activity, as well as (mainly for the gemfib rozil metabolite I) to their metal ion chelation capacities. In additi on, inhibition of HDL oxidation was associated with the preservation o f HDL-associated paraoxonase activity. We conclude that atorvastatin h ydroxy metabolites, and gemfibrozil metabolite I possess potent antiox idative potential, and as a result protect LDL, VLDL, and HDL from oxi dation. We hypothesize that in addition to their beneficial lipid regu lating activity, specific metabolites of both drugs may also reduce th e atherogenic potential of lipoproteins through their antioxidant prop erties. (C) 1998 Elsevier Science Ireland Ltd. All rights reserved.