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Oxygen radicals and rheumatoid disease
Antioxidant Therapy: Rheumatoid Diseases, Diseases of the Eye
20.1
OXYGEN RADICALS AND RHEUMATOID DISEASE Barry Halliwell Department of Biochemistry, King's College, Strand, London WC2R 2LS, UK My group is especially interested in the development of assays that can be used to study the rate of free radical reactions in vivo, especially in humans. Assays involving measurement of products of free radical attack upon uric acid, salicylate and the L- and D-isomers of phenylalanine will be described. "Fingerprinting" of oxidative damage to DNA by using gas chromatography-mass spectrometry with selected ion monitoring will also be discussed. Rheumatoid arthritis is an especially-useful disease in which to evaluate putative markers of free radical damage, since it is possibleto sample directly from the site of increased oxidant generation and also to vary the rate of oxidant generation in vivo over short time periods. Some representative results will be presented.
20.3
OXIDANTS AND ANTIOXIDANTS IN RHEUMATIC DISEASES Ingrid Emerit Institut biomedical des Cordeliers, CNRS and University Paris VI, France Rheumatic disorders include rheumatoid arthritis (RA), systemic lupus erythematosus, progressive systemic sclerosis, dermatomyositis and periarteritis nodosa. RA, the most frequent of these diseases, is also the most studied with respect to oxygen free radical generation, antioxidant tissue levels and possibilities of antioxidant treatment. The literature on these topics is reviewed and data from the author's laboratory are presented. Chromosome damaging material, so called clastogenic factors (CF) are released by cells in response to oxidative stress. Lipid peroxidation products and unconventional inosine nucleotides are components of these CF, which may be isolated from plasma, synovial fluid and cell culture supernatants. CF are not only at the origin of chromosome damage and DNA antibodies in these diseases, but also stimulate superoxide production by inflammatory cells. This leads to an autosustained process, which can be interrupted by superoxide dismutase and possibly by other antioxidants.
R E L A T I O N S H I P S B E T W E E N EYE LENS P R O T E I N OXIDATION, AGING, NUTRITION, C A T A R A C T AND P R O T E O L Y S I S A l l e n Taylor, Ruth D. Lipman, Koko Murakami, and J e s s i c a J a h n g e n Hodge U S D A H u m a n N u t r i t i o n R e s e a r c h Center on A g i n g at Tufts University, 711 W a s h i n g t o n St., Boston, MA 02111, U.S.A.
187
20.2
The solid mass of the eye lens is proteins called crystallins. Crystallins must remain intact to transmit and focus light on the retina. Upon aging and/or (photo)oxidative stress, lens proteins oxidize, aggregate, and p r e c i p i t a t e in o p a c i t i e s - - o r cataracts. In many cell types p r o t e a s e s remove damaged proteins, in part, via the highly selective, efficient u b i q u i t i n / A T P - d e p e n d e n t p r o t e o l y t i c pathway. An important component of this system is the lens high m o l e c u l a r w e i g h t p r o t e a s e - - o r proteasome. P r o t e a s o m e was isolated, and oxidative damage to c r y s t a l l i n was p e r f o r m e d as d e s c r i b e d (Free Rad. [1990] 86217-222). Rates of p r o t e o l y s i s of C o - i r r a d i a t e d alpha c r y s t a l l i n were 20>10>5>0 krad. H y d r o l y s i s of these substrates by p u r i f i e d p r o t e a s o m e did not require energy. However, ATPd e p e n d e n c e and formation of u b i q u i t i n c r y s t a l l i n c o n j u g a t e s were detected in a bovine lens epithelial supernatant. Support: USDA, contract #53-3K06-5-I0 and H o f f m a n n La-Roche Inc.
INFLUENCES OF DISEASE MODIFYING ANTI RREUMATIC DRUGS ON S U P E R O X I D E GENERATION F R O M THE HYPOXANTHINE-XANTHINE OXIDASE SYSTEM OR POLYHORPHONUCLEAR LEUKOCYTES T.Kaneko, T.Yoshikawa, H.Ichikawa, Y.Naito, H.Takano, S.Takahashi and M.Kondo First Department of Medicine, Kyoto Prefectural University of Medicine, Kyoto 602, Japan
The effects of disease modifying anti rheumatic drugs. (DMARDs) On superoxide re±ease from human polymorphonuclear leukocytes (PMNs) were investigated by Cypridana luciferin analog (CLA)dependent chemiluminescence assay. Auranofin, D-penicillamine, buci!iamine and sulphasalazopyridine had the inhibitory effects against superoxide release from PMNs stimulated by various stimulants. Especially auranofin had the most strongest inhibition of all. Gold sodium thiomalate and lobenzarit had littIe effects on superoxide release from PMNs. Furthermore, the influences of DMARDs on superoxide generation from the hypoxanthinexanthine oxidase system were studied by an electron spin resonance assay using 5,5-dimethyl-l-pyrroline-N-oxide (DMPO) as a spln trapper. The intensity of DMPO~OOH signal generated from the hypoxanthine-xanthlne oxidase system was decreased in the presence of Dpenicillamine and bucillamine. These results suggest that some DMARDs may have anti-inflammatory and anti-oxidative action due to scavenging superoxide radicals or due to inhibiting superoxide production.
20.4
20.1
OXYGEN RADICALS AND RHEUMATOID DISEASE Barry Halliwell Department of Biochemistry, King's College, Strand, London WC2R 2LS, UK My group is especially interested in the development of assays that can be used to study the rate of free radical reactions in vivo, especially in humans. Assays involving measurement of products of free radical attack upon uric acid, salicylate and the L- and D-isomers of phenylalanine will be described. "Fingerprinting" of oxidative damage to DNA by using gas chromatography-mass spectrometry with selected ion monitoring will also be discussed. Rheumatoid arthritis is an especially-useful disease in which to evaluate putative markers of free radical damage, since it is possibleto sample directly from the site of increased oxidant generation and also to vary the rate of oxidant generation in vivo over short time periods. Some representative results will be presented.
20.3
OXIDANTS AND ANTIOXIDANTS IN RHEUMATIC DISEASES Ingrid Emerit Institut biomedical des Cordeliers, CNRS and University Paris VI, France Rheumatic disorders include rheumatoid arthritis (RA), systemic lupus erythematosus, progressive systemic sclerosis, dermatomyositis and periarteritis nodosa. RA, the most frequent of these diseases, is also the most studied with respect to oxygen free radical generation, antioxidant tissue levels and possibilities of antioxidant treatment. The literature on these topics is reviewed and data from the author's laboratory are presented. Chromosome damaging material, so called clastogenic factors (CF) are released by cells in response to oxidative stress. Lipid peroxidation products and unconventional inosine nucleotides are components of these CF, which may be isolated from plasma, synovial fluid and cell culture supernatants. CF are not only at the origin of chromosome damage and DNA antibodies in these diseases, but also stimulate superoxide production by inflammatory cells. This leads to an autosustained process, which can be interrupted by superoxide dismutase and possibly by other antioxidants.
R E L A T I O N S H I P S B E T W E E N EYE LENS P R O T E I N OXIDATION, AGING, NUTRITION, C A T A R A C T AND P R O T E O L Y S I S A l l e n Taylor, Ruth D. Lipman, Koko Murakami, and J e s s i c a J a h n g e n Hodge U S D A H u m a n N u t r i t i o n R e s e a r c h Center on A g i n g at Tufts University, 711 W a s h i n g t o n St., Boston, MA 02111, U.S.A.
187
20.2
The solid mass of the eye lens is proteins called crystallins. Crystallins must remain intact to transmit and focus light on the retina. Upon aging and/or (photo)oxidative stress, lens proteins oxidize, aggregate, and p r e c i p i t a t e in o p a c i t i e s - - o r cataracts. In many cell types p r o t e a s e s remove damaged proteins, in part, via the highly selective, efficient u b i q u i t i n / A T P - d e p e n d e n t p r o t e o l y t i c pathway. An important component of this system is the lens high m o l e c u l a r w e i g h t p r o t e a s e - - o r proteasome. P r o t e a s o m e was isolated, and oxidative damage to c r y s t a l l i n was p e r f o r m e d as d e s c r i b e d (Free Rad. [1990] 86217-222). Rates of p r o t e o l y s i s of C o - i r r a d i a t e d alpha c r y s t a l l i n were 20>10>5>0 krad. H y d r o l y s i s of these substrates by p u r i f i e d p r o t e a s o m e did not require energy. However, ATPd e p e n d e n c e and formation of u b i q u i t i n c r y s t a l l i n c o n j u g a t e s were detected in a bovine lens epithelial supernatant. Support: USDA, contract #53-3K06-5-I0 and H o f f m a n n La-Roche Inc.
INFLUENCES OF DISEASE MODIFYING ANTI RREUMATIC DRUGS ON S U P E R O X I D E GENERATION F R O M THE HYPOXANTHINE-XANTHINE OXIDASE SYSTEM OR POLYHORPHONUCLEAR LEUKOCYTES T.Kaneko, T.Yoshikawa, H.Ichikawa, Y.Naito, H.Takano, S.Takahashi and M.Kondo First Department of Medicine, Kyoto Prefectural University of Medicine, Kyoto 602, Japan
The effects of disease modifying anti rheumatic drugs. (DMARDs) On superoxide re±ease from human polymorphonuclear leukocytes (PMNs) were investigated by Cypridana luciferin analog (CLA)dependent chemiluminescence assay. Auranofin, D-penicillamine, buci!iamine and sulphasalazopyridine had the inhibitory effects against superoxide release from PMNs stimulated by various stimulants. Especially auranofin had the most strongest inhibition of all. Gold sodium thiomalate and lobenzarit had littIe effects on superoxide release from PMNs. Furthermore, the influences of DMARDs on superoxide generation from the hypoxanthinexanthine oxidase system were studied by an electron spin resonance assay using 5,5-dimethyl-l-pyrroline-N-oxide (DMPO) as a spln trapper. The intensity of DMPO~OOH signal generated from the hypoxanthine-xanthlne oxidase system was decreased in the presence of Dpenicillamine and bucillamine. These results suggest that some DMARDs may have anti-inflammatory and anti-oxidative action due to scavenging superoxide radicals or due to inhibiting superoxide production.
20.4