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SUPEROXIDE-DISMUTASE THERAPY IN HYPERURICÆAMIC SYNDROMES
95
SUPEROXIDE-DISMUTASE THERAPY IN HYPERURICÆAMIC SYNDROMES
SiR,—The finding of Dr Rister and colleaguesl that children with rheumatoid arthritis show a relative deficiency of polymorphonuclear superoxide dismutase is also of interest in relation to gouty inflammatory disease. Electronically activated species of oxygen such as superoxide, hydroxyl radical, and singlet oxygen may play a key role in many inflammatory and degenerative processes. For example, as Rister et al. point out, the anti-inflammatory agent orgotein (’Ontosein’, Diagnostic Data Inc., Mountain View, California) is the pharmaceutical preparation of superoxide dismutase (S.0.D.).2.3 Besides its veterinary uses, orgotein has been reported to be effective in the treatment of several arthritic and urinary-tract inflammatory lesions in man.2.3 The pharmacological properties of S.O.D. (orgotein) may arise from its ability to destroy oxygen radicals produced by activated granulocytes as bactericidal agents.4.5 Production of oxygen radical species may be a key step in the control of the release from granulocyte lysosomes of various elements which mediate inflammation.’5 This may be because such oxidising species can exert a direct effect on the nucleotide cydases6.7 which apparently control the inflam-
Fig. 2-Extractability zones of normal
of
collagen by pepsin
across
the thirteen
and scoliotic discs.
L4-5 (.), L3-4 (8), L2-3 (·), Ll-2 the mean values in each zone.
(e).
The broken line represents
These results reflect qualitative differences in collagen from the scoliotic and normal disc tissue which could be interpreted in more than one way. Pepsin is reported to extract only type-u collagen from the intervertebral disc,4,5 and the normal disc profile in fig 2. reflects the distribution of type-u collagen across this structured Thus, the profile of the scoliotic tissue may be accounted for by a predominance of type-i collagen over type-n. Alternatively, pepsin at 4°C should cleave only the non-helical teleopeptide region of collagenso fig. 2. may also represent differences in these regions of the collagen molecule, which are important sites of cross-linking. Although a large proportion of matrix proteoglycans are removed before pepsin treatment, those remaining might influence pepsin extraction and account for the difference observed between normal and scoliotic tissue. However our results are interpreted they do point to significant qualitative differences between collagen from normal and scoliotic discs. Idiopathic scoliosis has a genetic background, through little is known about the mode of expression.7.8 Our results may point to a factor central to the pathogenesis of spinal curvature. For example, a cross-linking defect could be expected to render disc tissue less stable to deformation once curvature is initiated by other factors. This may explain why some curves progress and others do not, and for this frequent observation no scientific explanation has previously been
presented. Raymond Purves Research Laboratones, University of Sydney, Royal North Shore Hospital of Sydney, St. Leonards, New South Wales 2065, Australia 3.
G. R. BUSHELL P. GHOSH T. K. F. TAYLOR
Stegemann, H., Stalder, K. Clin. Chem. 1967, 18, 267. Osebold, W. R , Pedrini, V. Biochim. biophys. Acta, 1976, 434, 390. Eyre, D. R., Muir, H. ibid. 1977, 492, 29. Miller, E. J. Biochemistry, 1972, 11, 490. Francis, M. J. O., Sanderson, M. C., Smith, R. Clin. Sci. mol. Med. 1976, 51, 467. 8. Bradford, D. S., Degema, T. R., Brown, D. M. Clin. Orthop. rel. Res. 1977, 126, 111.
4. 5. 6. 7.
matory process.8 The role of uric acid in physiological function may similarly arise from its electron-transfer properties.9-" Likewise, uric acid can catalyse radical oxidations1o (putative evidence for oxygen radical formation, although in later [unpublished] work we have found that these species are primarily not superoxide radicals). Taking these data in the context of a role of oxygen radical species in inflammatory processes, it seems reasonable to suggest that oxygen radical production may play a part in the aetiology of gouty inflammatory disease and perhaps in other disorders of purine metabolism such as the
Lesch-Nyhan syndrome. 10, 11 There is experimental support for this suggestion. Lowrey 12 found that orgotein (whose sole known activity is the destruction of oxygen radicals) is effective in the treatment of a steroidnon-responsive gouty inflammatory disorder in Dalmatian dogs. Added support is given by the observation that such animals are typically both hyperpigmented and deaf, as predicted’O,"
on the basis of the common electron-transfer properof uric acid and other compounds (e.g., iron in haemochromatosis) which are associated with these symptoms. It follows that orgotein might likewise be effective in the treatment of such disorders of purine metabolism in man as the Lesch-Nyhan syndrome or acute gouty nephropathy, which sometimes are difficult to control by pharmacological methods. The agent might also be effective in the treatment of diseases such as Usher’s syndrome in which there is also indirect evidence for a free radical component." Orgotein seems to have very few side-effects2.3 and so could be used with
ties
safety. Supported by
a
grant from the Retina Research
Foundation,
Houston, Texas. Department of Ophthalmology, Baylor College of Medicine, Houston, Texas 77030, U.S.A.
Department of Physics, University of Texas Cancer Center Houston 1. 2.
PETER H. PROCTOR DONALD S. KIRKPATRICK
JOHN
E. MCGINNESS
Rister, M., Bauermeister, K., Gravert, U., Gladtke, E. Lancet, 1978, i, 1094. Huber, W., Menander-Huber, K. B., Saifer, M. G. P., Dang, P. H.-C. in Perspectives in Inflammation, (edited by D. A. Willoughby, J. P. Giroud, and G. P. Velo.); p. 527. Lancaster, 1977. 3. Menander-Huber, K. B., Huber, W. in Superoxide and Superoxide Dismutases (edited by A. M. Michelson, J. McCord, and I. Fridovich); p. 537. London, 1977. 4. Salin, M. L., McCord, J. M. J. clin. Ivest. 1975, 56, 1319. 5. Oyanagui, Y. Biochem. Pharmac. 1976, 25, 1465. 6. Mukherjee, S. P., Lynn, W. S. Archs Biochem. Biophys. 1977, 184, 69. 7. Mittol, C. K. Murad, F. J. cycl. Nucleotide Res. 1977, 3, 381. 8. Davies, P. Ag. Actions, 1978, suppl. 3, p. 107. 9. Proctor, P. Nature, 1970, 228, 868. 10. Proctor, P. Physiol. Chem. Phys. 1972, 4, 349. 11. Proctor, P. Pigment Cell, 1976, 3, 378. 12. Lowrey, J. C Vet. Med. 1976, 71, 289.
’
-
SUPEROXIDE-DISMUTASE THERAPY IN HYPERURICÆAMIC SYNDROMES
SiR,—The finding of Dr Rister and colleaguesl that children with rheumatoid arthritis show a relative deficiency of polymorphonuclear superoxide dismutase is also of interest in relation to gouty inflammatory disease. Electronically activated species of oxygen such as superoxide, hydroxyl radical, and singlet oxygen may play a key role in many inflammatory and degenerative processes. For example, as Rister et al. point out, the anti-inflammatory agent orgotein (’Ontosein’, Diagnostic Data Inc., Mountain View, California) is the pharmaceutical preparation of superoxide dismutase (S.0.D.).2.3 Besides its veterinary uses, orgotein has been reported to be effective in the treatment of several arthritic and urinary-tract inflammatory lesions in man.2.3 The pharmacological properties of S.O.D. (orgotein) may arise from its ability to destroy oxygen radicals produced by activated granulocytes as bactericidal agents.4.5 Production of oxygen radical species may be a key step in the control of the release from granulocyte lysosomes of various elements which mediate inflammation.’5 This may be because such oxidising species can exert a direct effect on the nucleotide cydases6.7 which apparently control the inflam-
Fig. 2-Extractability zones of normal
of
collagen by pepsin
across
the thirteen
and scoliotic discs.
L4-5 (.), L3-4 (8), L2-3 (·), Ll-2 the mean values in each zone.
(e).
The broken line represents
These results reflect qualitative differences in collagen from the scoliotic and normal disc tissue which could be interpreted in more than one way. Pepsin is reported to extract only type-u collagen from the intervertebral disc,4,5 and the normal disc profile in fig 2. reflects the distribution of type-u collagen across this structured Thus, the profile of the scoliotic tissue may be accounted for by a predominance of type-i collagen over type-n. Alternatively, pepsin at 4°C should cleave only the non-helical teleopeptide region of collagenso fig. 2. may also represent differences in these regions of the collagen molecule, which are important sites of cross-linking. Although a large proportion of matrix proteoglycans are removed before pepsin treatment, those remaining might influence pepsin extraction and account for the difference observed between normal and scoliotic tissue. However our results are interpreted they do point to significant qualitative differences between collagen from normal and scoliotic discs. Idiopathic scoliosis has a genetic background, through little is known about the mode of expression.7.8 Our results may point to a factor central to the pathogenesis of spinal curvature. For example, a cross-linking defect could be expected to render disc tissue less stable to deformation once curvature is initiated by other factors. This may explain why some curves progress and others do not, and for this frequent observation no scientific explanation has previously been
presented. Raymond Purves Research Laboratones, University of Sydney, Royal North Shore Hospital of Sydney, St. Leonards, New South Wales 2065, Australia 3.
G. R. BUSHELL P. GHOSH T. K. F. TAYLOR
Stegemann, H., Stalder, K. Clin. Chem. 1967, 18, 267. Osebold, W. R , Pedrini, V. Biochim. biophys. Acta, 1976, 434, 390. Eyre, D. R., Muir, H. ibid. 1977, 492, 29. Miller, E. J. Biochemistry, 1972, 11, 490. Francis, M. J. O., Sanderson, M. C., Smith, R. Clin. Sci. mol. Med. 1976, 51, 467. 8. Bradford, D. S., Degema, T. R., Brown, D. M. Clin. Orthop. rel. Res. 1977, 126, 111.
4. 5. 6. 7.
matory process.8 The role of uric acid in physiological function may similarly arise from its electron-transfer properties.9-" Likewise, uric acid can catalyse radical oxidations1o (putative evidence for oxygen radical formation, although in later [unpublished] work we have found that these species are primarily not superoxide radicals). Taking these data in the context of a role of oxygen radical species in inflammatory processes, it seems reasonable to suggest that oxygen radical production may play a part in the aetiology of gouty inflammatory disease and perhaps in other disorders of purine metabolism such as the
Lesch-Nyhan syndrome. 10, 11 There is experimental support for this suggestion. Lowrey 12 found that orgotein (whose sole known activity is the destruction of oxygen radicals) is effective in the treatment of a steroidnon-responsive gouty inflammatory disorder in Dalmatian dogs. Added support is given by the observation that such animals are typically both hyperpigmented and deaf, as predicted’O,"
on the basis of the common electron-transfer properof uric acid and other compounds (e.g., iron in haemochromatosis) which are associated with these symptoms. It follows that orgotein might likewise be effective in the treatment of such disorders of purine metabolism in man as the Lesch-Nyhan syndrome or acute gouty nephropathy, which sometimes are difficult to control by pharmacological methods. The agent might also be effective in the treatment of diseases such as Usher’s syndrome in which there is also indirect evidence for a free radical component." Orgotein seems to have very few side-effects2.3 and so could be used with
ties
safety. Supported by
a
grant from the Retina Research
Foundation,
Houston, Texas. Department of Ophthalmology, Baylor College of Medicine, Houston, Texas 77030, U.S.A.
Department of Physics, University of Texas Cancer Center Houston 1. 2.
PETER H. PROCTOR DONALD S. KIRKPATRICK
JOHN
E. MCGINNESS
Rister, M., Bauermeister, K., Gravert, U., Gladtke, E. Lancet, 1978, i, 1094. Huber, W., Menander-Huber, K. B., Saifer, M. G. P., Dang, P. H.-C. in Perspectives in Inflammation, (edited by D. A. Willoughby, J. P. Giroud, and G. P. Velo.); p. 527. Lancaster, 1977. 3. Menander-Huber, K. B., Huber, W. in Superoxide and Superoxide Dismutases (edited by A. M. Michelson, J. McCord, and I. Fridovich); p. 537. London, 1977. 4. Salin, M. L., McCord, J. M. J. clin. Ivest. 1975, 56, 1319. 5. Oyanagui, Y. Biochem. Pharmac. 1976, 25, 1465. 6. Mukherjee, S. P., Lynn, W. S. Archs Biochem. Biophys. 1977, 184, 69. 7. Mittol, C. K. Murad, F. J. cycl. Nucleotide Res. 1977, 3, 381. 8. Davies, P. Ag. Actions, 1978, suppl. 3, p. 107. 9. Proctor, P. Nature, 1970, 228, 868. 10. Proctor, P. Physiol. Chem. Phys. 1972, 4, 349. 11. Proctor, P. Pigment Cell, 1976, 3, 378. 12. Lowrey, J. C Vet. Med. 1976, 71, 289.
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