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Volume 271, Number 51, Issue of December 20, 1996 pp. 32714-32721
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.

3-Hydroxyanthranilic Acid Is an Efficient, Cell-derived Co-antioxidant for alpha -Tocopherol, Inhibiting Human Low Density Lipoprotein and Plasma Lipid Peroxidation

(Received for publication, August 5, 1996, and in revised form, September 27, 1996)

Shane R. Thomas , Paul K. Witting and Roland Stocker

From the Biochemistry Unit, The Heart Research Institute, 145 Missenden Road, Camperdown, Sydney, New South Wales 2050, Australia

alpha -Tocopherol (alpha -TOH) can promote lipid peroxidation in human low density lipoprotein (LDL) unless co-antioxidants are present that eliminate the chain-carrying alpha -tocopheroxyl radical (alpha -TO·) (Bowry, V. W., Mohr, D., Cleary, J., and Stocker, R. (1995) J. Biol. Chem. 270, 5756-5763). Interferon-gamma inhibits human monocyte/macrophage-facilitated LDL lipid peroxidation via induction of cellular tryptophan degradation and production and release of 3-hydroxyanthranilic acid (3HAA) (Christen, S., Thomas, S. R., Garner, B., and Stocker, R. (1994) J. Clin. Invest. 93, 2149-2158). We now report on the mechanism of antioxidant action of 3HAA. 3HAA directly reduced alpha -TO· in UV-exposed micellar dispersions of alpha -TOH or in LDL incubated with soybean 15-lipoxygenase (SLO), as assessed by electron paramagnetic resonance spectroscopy. 3HAA did not inhibit SLO enzyme activity. Anthranilic acid, which lacks the phenoxyl group, was incapable of reducing alpha -TO·. 3HAA dose-dependently inhibited the peroxidation of surface phospholipids and core cholesteryl esters in LDL exposed to SLO, peroxyl radicals (ROO·), or Cu2+; oxidants that convert alpha -TOH to alpha -TO·. In all cases, sparing of LDL's alpha -TOH, but not ubiquinol-10 (CoQ10H2), was observed until the majority of 3HAA was consumed. Addition of 3HAA or ascorbate prevented further consumption of alpha -TOH and accumulation of lipid hydroperoxides when added to aqueous or lipophilic ROO·-oxidizing LDL after complete and partial consumption of CoQ10H2 and alpha -TOH, respectively. In contrast, addition of urate, an efficient ROO· scavenger incapable of scavenging alpha -TO·, did not efficiently inhibit ongoing lipid peroxidation. Oxidation of 3HAA-supplemented human plasma by aqueous ROO· resulted in the successive consumption of ascorbate, CoQ10H2, 3HAA, bilirubin, alpha -TOH, and urate. Lipid peroxidation was prevented as long as ascorbate, CoQ10H2, and 3HAA were present, but subsequently proceeded as a free-radical chain reaction concomitant with alpha -TOH, bilirubin, and urate consumption. Addition of 3HAA to aqueous ROO·-oxidizing plasma, after complete consumption of ascorbate and CoQ10H2, strongly inhibited ongoing lipid peroxidation and consumption of alpha -TOH, bilirubin, and urate immediately and as efficiently as did ascorbate. These findings demonstrate that 3HAA is a highly efficient co-antioxidant for plasma lipid peroxidation by virtue of its ability to interact with alpha -TO· in lipoproteins. Since interferon-gamma is the principal inducer of tryptophan degradation and release of 3HAA by monocytes/macrophages, this may represent a localized extracellular antioxidant defense against LDL oxidation in inflammation.


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