期刊
BIOCHEMICAL PHARMACOLOGY
卷 64, 期 11, 页码 1661-1667出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/S0006-2952(02)01391-6
关键词
ursodeoxycholic acid; antioxidant; hydroxyl radical; iron; lipid peroxidation; oxidative stress
We have investigated potential antioxidant properties of the clinically relevant bile acid UDCA, which reaches therapeutic concentrations up to 0.09 and 29 mM, respectively, in human plasma and bile. UDCA was an excellent scavenger of OH. generated by FeCl3-EDTA, H2O2 and ascorbate in the deoxyribose oxidation test, showing ICmin in and IC50 values of 0.02 and 0.2 mM, respectively, and a second-order rate constant for reaction with OH. of 2 0.1 x 10(10) M-1 s(-1). Notably, the drug could enhance at 1.5 mM concentration the antioxidant capacity of human bile against OH.-induced deoxyribose oxidation. UDCA also showed antioxidant effects in the deoxyribose test performed with nonchelated iron ions, such as Fe2+ plus H2O2 (ICmin: 7 MM, IC50: 20 mM) or Fe3+ plus H2O2 and ascorbate (ICmin: 0.3 mM, IC50: 5 mM), and inhibited ferrozine-Fe2+ and desferrioxamine-Fe3+ complexes formation with IC50 values of, respectively, 12 and 0.3 mM, indicating that the drug interacts more with iron(III) than with iron(II). Moreover, UDCA significantly inhibited phospholipid liposome peroxidation induced by the OH.-generating system FeC13-EDTA, H2O2 and ascorbate (ICmin: 0.75 mM, IC50: 3 mM), and by peroxyl radicals generated in the aqueous phase by AAPH (ICmin: 8 mM, IC50: 14 mM). UDCA, even at 25 MM concentration, was ineffective on the lipoperoxidation mediated by Fe2+ alone, but at the same concentration counteracted significantly that by Fe3+ plus ascorbate, further pointing to its preferential antioxidant interaction with iron(III). In conclusion, UDCA has direct antioxidant properties, which are especially relevant against Fe3+- and OH.-dependent biomolecular oxidative damage; such properties are evident at therapeutically relevant drug concentrations, suggesting that UDCA could act as an antioxidant in vivo. (C) 2002 Elsevier Science Inc. All rights reserved.
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