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
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.