LIPID PEROXIDATION, OXYGEN RADICALS, CELL DAMAGE, AND ANTIOXIDANT THERAPY

1396 level in English. I make no apology for the 200 hours set aside for learning the use of a keyboard and presentation and retrieval of information, because there should be no question of the provision of secretaries to support the rehabilitation worker. However, it may well be that such skills will be increasingly taught at school, leaving more time for the acquisition of the more practical helping skills, to which 300 hours are already given in the proposed curriculum. There remains the question of what our "DHSS" diplomats should be called. I favour "social helper" or "practical helper", as long as it is clearly understood that they will be helping clients, and not helping professionals to help clients.

CONCLUSION

unlikely that professional speech therapists, physiotherapists, occupational therapists, health visitors, or social workers will welcome such proposals from a neurologist. And if the ideas set out in this paper find favour, it will be some time before enough social helpers are available to take on the functions suggested here. Their contribution will have to be evaluated at an early stage, to avoid the present situation of large bands of employees of health service and local authorities undertaking actions of unproven efficacy or It

is

benefit.

I thank the friends of the late Michael Wheeler for some financial assistance.

Occasional

Survey

LIPID PEROXIDATION, OXYGEN RADICALS, CELL DAMAGE, AND ANTIOXIDANT THERAPY B. HALLIWELL

Department of Biochemistry, King’s College, London WC2R 2LS

JOHN M. C. GUTTERIDGE National Institute for Biological Standards and Control, London NW3 6RB

THE detailed description of the mechanism’ of super oxide dismutase action and the proposed role of hydroxyl radicals in natural killer cell activity2 recently published in Nature are further examples of the extensive information now available on the biomedical importance of oxygen-derived species such

superoxide radical, hydrogen peroxide, and hydroxyl radical, and the enzymes that protect against these species. The production of oxygen-derived species by activated phagocytes3 and by other mechanisms4within the human body is now firmly established, as is the damage that radicals such as hydroxyl can do to cellular molecules (eg, fragmentation of DNA leading to mutations).4,5 Exposure of as

oxygen radicals stimulates the process of "lipid peroxidation"." In this process the fatty-acid sidechains of the membrane lipids, especially those containing two or more carbon-carbon double bonds, are oxidised to hydroperoxides. In the presence of metal catalysts hydroperoxides decompose to form a complex mixture of hydrocarbons and cytotoxic aldehydes.6 Polyunsaturated lipids are also components of many foodstuffs-eg, fish and vegetable oils. Indeed, peroxidation of food lipids, leading to cell membranes

to

REFERENCES

Population Censuses and Surveys. Population projections 1978-2018 London. HM Stationery Office, 1980. 2. Hunt A The elderly at home. London: HM Stationery Office, 1978 3. Grimley Evans J. Demographic implications for the planning of services in the services in the United Kingdom In: Kinnaird J, Brotherston J, Williams J, eds. The provision of care for the elderly. Edinburgh: Churchill Livingstone, 1981: 8-13. 4. Brocklehurst JC, Andrews K, Morris P, Richards BR, Laycock PL. Why admit stroke patients to hospital. Age Ageing 1978; 7: 100-08. 5. Carstairs V Our elders. In: Shegog RFA, ed. The impending crisis of old age. Oxford: Oxford University Press, 1981 29-42. 6. Social trends no 13. London. HM Stationery Office, 1983. 7. Gatherer AA. Support in the home. In: Shegog RFA, ed. The impending crisis of old age. Oxford: Oxford University Press, 1981: 55-69. 8. Department of Health and Social Security. The remedial professions. A report by a working party set up in March 1973 by the Secretary of State for Social Services (the McMillan report). London HM Stationery Office, 1973. 9. Illsley R. Sociological aspects. In Kinnaird J, Brotherston J, Williams J, eds. The provision of care for the elderly Edinburgh: Churchill Livingstone, 1981. 211-16 10. Brewer C, Lait J Can social work survive. London: Temple Smith, 1980. 1 1. Garraway WM, Akhtar AJ, Hockey L, et al. Management of acute stroke in the elderly: follow-up ofa controlled trial. Br Med J 1980; 281: 827-29. 12. Smith DS, Goldenberg E, Ashburn A, et al. Remedial therapy after stroke: a randomised controlled trial. Br Med J 1981; 282: 517-20. 13. David R, Enderby P, Bainton D Treatment of acquired aphasia: Speech therapists and volunteers compared. J Neurol Neurosurg Psychiat 1982; 45: 957-61. 14. Ward AWM. Physiotherapists—career patterns and attitudes. Health Trends 1979; 11: 1. Office of

14-17.

Johnson H, Paterson C. Training for the remedial professions A report on therapists’ attitudes to training. London. King’s Fund, 1975; no 14036. 16 Dingwall R. The social organisation of health visitor training. London: Croom Helm, 15.

1977

NJ, Jones DA, Victor CR. Effect of health visitors working with elderly patients general practice: a randomised controlled trial Br MedJ 1984; 288: 369-72. Hopkins AP. The need for speech therapy for dysphasia following stroke. Health

17 Vetter in

18.

Trends 1975, 7: 58-60. 19 Brocklehurst JC, Andrews K, Richards B, et al. How much physical therapy for patients with stroke? Br Med J 1978; i: 1307-10. 20 Helander E. Towards a multipurpose rehabilitation therapist. Rehabilitation 1980; 1: 26-29. 21 Social services facing changes Times Feb 18, 1983.

rancidity, has been extensively studied by food chemists, who have developed several "antioxidants". In general terms, antioxidants are compounds that inhibit lipid peroxidation by interfering with the chain reaction of peroxidation’ and/or by scavenging reactive oxygen radicals.4 Popular antioxidants include vitamin E (a-tocopherol), ethoxyquin, propyl gallate, butylated hydroxyanisole, and butylated hydroxytoluene. Selenium is often listed as a dietary antioxidant because it is required for the formation of active glutathione peroxidase, an enzyme that removes hydrogen peroxide in vivo and helps to prevent hydroxyl radical formation.4 This enzyme might also offer some protection against lipid peroxidation. Many studies have implicated oxygen radicals and lipid peroxidation in ageing and various diseases, including cancer, multiple sclerosis, Parkinson’s disease, Fanconi’s anaemia, and lupus. "Free radical theories" of ageing and disease abound. Oxygen radicals and lipid peroxidation have been suggested to account for the toxic action of a wide range of compounds, such as paraquat, doxorubicin, ethanol, alloxan, and anilides found in adulterated Spanish cooking oils.’ Sometimes the evidence is sufficient to support these in the actions of alloxanand carbon tetrachloridé,9), but often it consists only of a demonstration that "lipid peroxidation" in animal cells, tissues, or body fluids is increased as they age, in disease states, or after administration of toxins. The unspoken assumptioni° behind much of this work is that the sequence of events operating is

suggestions (most notably

Disease or toxin

---> -

Free radicals

Lipid peroxidation

-i>-

However, it was established many years agol to

have been

forgotten)

that

disrupted

Tissue damage and death

(1)

l-i4 (but appears tissues

undergo

1397 more quickly than healthy ones. For example, the time taken for a joint of meat to go rancid as compare compared with that taken by minced meat. Lipid peroxides accumulate in a brain homogenate standing on the laboratory bench much more quickly than they do in a whole brain. Reasons for this increased peroxidisability of damaged tissues include inactivation of some antioxidants’’and the release of metal ions (especially iron and copper) from storage sites within the cells, eg, as metalloenzymes are destroyed by released lysosomal proteases. Metal ions are essential for lipid peroxidation stimulated by oxygen radicals4 and they facilitate the decomposition of lipid peroxides to cytotoxic

peroxidation

products.6 We therefore suggest that, with few exceptions,8,9 many of the published reports implicating lipid peroxidation in human disease and toxicology are better explained by the reaction sequence Disease toxin

degenerative disorders? The results clearly show an improvement of many of the disease symptoms in certain patients for variable periods of time. A likely explanation is that the diseases cause tissue degeneration, the diseased tissues peroxidise more rapidly than normal (sequence 2) and the cytotoxic end-products of lipid peroxidation6 do some damage to healthy tissues. Antioxidants help by preventing this secondary damage, but they cannot halt the primary

pathology of the disease. This does suggest, however, that correctly applied antioxidant therapy will have some beneficial effects in many degenerative diseases, and, in the absence of any more specific therapy, should be tested. It would not be expected to effect a cure. In the same way, ageing tissues probably peroxidise more quickly than normal and antioxidants might minimise the resulting damage, 19 but they will not halt the ageing process.16 CONCLUSION

or

Cell

lipid (2) damage increased ) or death peroxidation

toxin or disease that causes tissue damage may well measurable increases in lipid peroxidation as a consequence of that damage. Antioxidant therapy will not cure a disease unless that disease is caused by increased radical formation. With the possible exception of Keshan disease, no human disease caused by increased radical formation has been discovered as yet. Antioxidant therapy may alleviate the physical signs of degenerative diseases such as multiple sclerosis, muscular dystrophy, Parkinson’s disease, or neuronal ceroid lipofuscinoses only to the extent that the tissue damage is made worse by free-radical reactions and the antioxidant administered can reach the correct site of action. Such therapy can be justified, as it has been for neuronal ceroid lipofuscinoses, 18 in the absence of knowledge of the true cause of these diseases. The beneficial effects may be marginal and/or of short duration.

Any

cause

than they are by sequence (1). In particular, we suggest that the variable and contradictory results that have been published on the role of lipid peroxidation in the toxicity of paraquat, ethanol, and paracetamol show that sequence (2) is a much more likely explanation of these results than is sequence

(1). ANTIOXIDANT THERAPY

If ageing, human disease, and the action of toxins were due increased lipid peroxidation, then antioxidants would have a pronounced protective effect. Of course, some antioxidants to

administered

to

humans will

not

reach the

correct

site of

action, but given the wide range of antioxidants available some should be found that will have an effect. Indeed, many of the symptoms of vitamin E deficiency in animals can be reversed by feeding synthetic antioxidants. 15 Superoxide dismutase protects against alloxan toxicity8 and other antioxidants protect against the action of carbon tetrachloride.6,99 On the other hand, the effects of dietary antioxidants on the maximum lifespan of small mammals are slight,16 which might be taken to mean that the ageing process cannot be halted by stopping lipid peroxidation. There is one human disease that perhaps illustrates this point. Keshan disease, a severe cardiomyopathy, was until recently very common in areas of China.17 It is caused by inadequate dietary intake of selenium. Although not proven, it is tempting to attribute the pathology of Keshan disease to lack of cardiac glutathione peroxidase activityY Selenium supplementation of the diet of the populations at risk almost entirely prevents the disease from developing. Similarly, if ageing in mammals or degenerative diseases were indeed caused by increased free-radical reactions than one might expect similar dramatic effects of at least some antioxidants provided that they were given before irreversible damage had occurred. Such dramatic effects are seen neither in studies of the ageing of laboratory animals (see above) nor in human disease. For example, in Finland antioxidant therapy has been used to treat hereditary degenerative diseases of the nervous system from an early age.18 The diseases are not cured or prevented from developing by there treatment regimens, which include vitamin E and selenium. Presumably, therefore, the diseases are not caused by increased radical formation. Should antioxidant therapy therefore be dismissed as worthless in the treatment of

Correspondence

should be addressed

to

B. H.

REFERENCES 1. Pain RH. Dressing the SOD. Nature 1983; 306: 228. 2. Suthanthiran M, Solomon SD, Williams PS, Rubin AL, Novogrodsky A, Stenzel KH. Hydroxyl radical scavengers inhibit human natural killer cell activity. Nature 1984; 307: 276-78. 3. Tauber AI, Borregaard N, Simons E, Wright J. Chronic granulomatous disease: a syndrome of phagocyte oxidase deficiencies. Medicine 1983; 62: 286-309. 4 Halliwell B, Gutteridge JMC Free radicals in biology and medicine. Oxford: Clarendon Press, 1984. 5. Fridovich I. Superoxide radical: an endogenous toxicant. Annu Rev Pharmacol Toxicol

1983; 23: 239-57. DCH, Slater TF, eds. Free radicals, lipid peroxidation and cancer. London: Academic Press, 1982. 7. Root-Bernstein RS, Westall FC. Mycoplasma pneumoniae and a dual aetiology for Spanish oil syndrome. Nature 1983; 301: 178. 8. Grankvist K, Marklund S, Taljedal IB. Superoxide dismutase is a prophylactic against alloxan diabetes. Nature 1981, 294: 158-60. 9. Reddrop CJ, Cheesman KH, Slater TF Correlations between common tests for assessment of liver damage: indices of the hepatoprotective activity of promethazine in carbon tetrachloride hepatotoxicity. Cell Biochem Funct 1983; 1: 55-63. 10. Smith MT, Thor H, Orrenius S. The role of lipid peroxidation in the toxicity of foreign compounds to liver cells. Biochem Pharmacol 1983, 32: 763-64 11. Barber AA. Mechanisms of lipid peroxide formation in rat tissue homogenates. Radial Res 1963; suppl 3. 33-43. 12. Barber AA, Bernheim F Lipid peroxidation: its measurement, occurrence and significance in animal tissues. Adv Gerontol Res 1967; 2: 355-403 13. Gutteridge JMC, Stocks J. Peroxidation of cell lipids. Med Lab Sci 1976; 33: 281-85. 14. Stocks J. Studies of the anti-oxidant component of human serum and red cells. PhD thesis, University of London, 1982 15. de Duve C, Hayaishi O, eds. Tocopherol, oxygen and biomembranes Amsterdam: Elsevier/North Holland, 1978. 16. Pryor WA. Free radical biology: xenobiotics, cancer and aging. Ann NY Acad Sci 1982; 6. McBrien

393: 1-22 17.

Diplock AT. Metabolic and functional defects in selenium deficiency. Phil Trans R Soc Land 1981; B294: 105-17

Halliwell B, Westermarck T Increased non-proteinprotection against superoxide-radical damage in cerebrospinal fluid from patients with neuronal ceriod lipofuscinoses. Lancet 1982, ii: 459-60. 19. Harman D. The ageing process Proc Natl Acad Sci USA 1981; 78: 7124-28. 18

Gutteridge JMC, Rowley DA, bound

iron

and

decreased