Q J Med 2001; 94: 445-448
© 2001 Association of Physicians
Commentary |
Salicylic acid: a link between aspirin, diet and the prevention of colorectal cancer
From the Departments of Biochemistry and Medicine, Dumfries and Galloway Royal Infirmary, Dumfries, UK
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Summary |
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Aspirin was introduced into clinical practice more than 100 years ago. This unique drug belongs to a family of compounds called the salicylates, the simplest of which is salicylic acid, the principal metabolite of aspirin. Salicylic acid is responsible for the anti-inflammatory action of aspirin, and may cause the reduced risk of colorectal cancer observed in those who take aspirin. Yet salicylic acid and other salicylates occur naturally in fruits and plants, while diets rich in these are believed to reduce the risk of colorectal cancer. Serum salicylic acid concentrations are greater in vegetarians than non-vegetarians, and there is overlap between concentrations in vegetarians and those taking low-dose aspirin. We propose that the cancer-preventive action of aspirin is due to its principal metabolite, salicylic acid, and that dietary salicylates can have the same effect. It is also possible that natural salicylates contribute to the other recognized benefits of a healthy diet.
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Introduction |
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Aspirin (acetylsalicylic acid) occupies a unique place in medicine. Since its clinical introduction in 1899, we have become familiar with this drug and its many surprising effects, including reduced risk of cardiovascular disease and possibly colorectal cancer, as well as its analgesic, anti-inflammatory and anti-platelet actions. Aspirin is thought to reduce the risk of colorectal cancer, perhaps by as much as 40%, a property that is shared by other non-steroidal anti-inflammatory drugs (NSAIDS).1,2 Evidence for this effect comes from multiple epidemiological studies, most of which have found that aspirin reduces the risk of colorectal adenoma3 and carcinoma,4 as well as from animal models where aspirin inhibits chemical-induced colonic carcinogenesis.5,6 Aspirin belongs to a family of compounds called the salicylates, the simplest of which is salicylic acid. Salicylic acid is the principal metabolite of aspirin, aspirin having a half-life of <30 min.7 Many of the salicylates share the same properties as aspirin, although its anti-platelet action is specific. Extracts of plants, such as the willow and meadowsweet (which contain various compounds metabolized to salicylic acid), as well as salicylic acid prepared synthetically, pre-dated aspirin in the treatment of inflammatory conditions. The occurrence of ‘natural’ salicylates, such as salicylic acid present in strawberries and other fruit, was discussed in the Lancet of 1903,8 and the matter of whether ‘natural’ salicylates were superior to synthetic salicylates was the subject of a JAMA editorial in 19139 (no superiority could be shown).
Today's healthy diet mantra of, ‘five servings of fruit and vegetables a day’, may well be good advice yet, other than in the most vague general terms, we are unable to explain its basis. Nutritional research has already examined, and continues to assess, various plant constituents. However, the responsible constituent(s) for producing better health remains, as yet, elusive. One compound which we believe should be more fully considered is salicylic acid, a compound which plays a central role in the development of local and systemic disease resistance to pathogen infection in plants.10 Salicylic acid is present in fruits and vegetables, with herbs and spices being a particular rich source.11,12
Janssen et al.13 have concluded that a normal diet provides only 0–6 mg of salicylates daily, and no measurable aspirin.12 The estimated dietary intake of salicylates was based on urinary analysis in 17 volunteers eating a wide variety of diets, and it was suggested that the intake was probably too low to affect disease risk. Urinary salicylate concentrations, however, provide little information on blood or tissue concentrations, since salicylic acid is extensively metabolized, and its renal excretion is influenced by factors such as urinary pH and flow, and the presence of other organic acids.7 In a study of 10 subjects given 40.5 mg aspirin, the mean peak plasma salicylic acid concentration was 11.8 µmol/l, with a SD of 8.18 µmol/l, indicating a large inter-individual variability in the salicylic acid concentrations after the same dose of aspirin.14 In addition, no studies have investigated whether a dietary salicylate intake of a few milligrams has health benefits or not. Paterson et al.15 identified salicylic acid and two other salicylates as normal constituents of serum in individuals not taking salicylate drugs. Salicylates were found to be present in every serum sample analysed. The same group went on to show that higher serum concentrations of salicylic acid were present in vegetarians than in non-vegetarians, and that there was overlap in the serum concentrations between vegetarians and those taking aspirin (75 mg daily).16
We postulate that dietary salicylates have beneficial properties because of their effect on the ‘inflammatory process’, a concept that would explain why both aspirin and a diet rich in fruits and vegetables help prevent colorectal cancer (Figure 1
), and probably other inflammatory diseases. Inflammatory processes are involved in carcinogenesis and cancer growth.17 Most human colorectal cancers express high levels of cyclooxygenase-2 (COX-2), a key enzyme catalysing the conversion of arachidonic acid into prostaglandins, contributing to the inflammatory response.18 There are two isoforms of COX; COX-1 is constitutively expressed in platelets and other tissues, and COX-2 is an enzyme induced by various growth factors, interleukins and lipopolysaccharides in inflammation, but which may be also present constitutively in some tissues.19 COX-2 expression in animal models is associated with tumour progression.20 Aspirin and the other NSAIDS are believed to reduce the risk of colorectal cancer, at least in part, by inhibiting COX-2 activity.21
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The anti-inflammatory activity of aspirin is due to its major metabolite, salicylic acid,22 yet salicylic acid is inactive against COX in either broken cells or purified enzyme preparations.23 It was, however, found to be a weak inhibitor of both COX isoforms in intact cells. How then does salicylic acid exert its anti-inflammatory action? Salicylic acid appears to inhibit the transcription of the COX-2 gene,24,25 inhibition occurring at concentrations found in those taking low-dose aspirin. The salicylic acid concentration which inhibited COX-2 transcription by 50% was estimated to be 5000 nmol/l, although even concentrations as low as 100 nmol/l appeared to have some effect.25 The median serum concentration of salicylic acid in a group of vegetarians not taking salicylate drugs was 107 nmol/l, with the highest concentration being 2468 nmol/l.16 We propose that serum concentrations of salicylic acid, arising at least in part from dietary plant sources, are sufficiently high in some cases to reduce COX-2 gene transcription. This proposed action of dietary salicylates does not exclude the possibility that other components of fruits and vegetables have similar properties, or that the salicylates have actions in addition to their inhibition of COX-2, as there is evidence that NSAIDS may have a chemopreventive effect through COX-independent mechanisms.21
In plants subjected to pathogen attack, salicylic acid contributes to the containment of infection, the activation of cell death and the induction of local and systemic disease resistance.26 Salicylic acid achieves these effects through increasing defence gene expression, potentiating cell death and altering the expression or activity of various enzymes. Many of these actions occur in plants at salicylic acid concentrations comparable to those present in patients who take low-dose aspirin. It is possible that some genes common to plants and animals which govern ancient conserved proteins (or regions thereof), are modulated by salicylic acid.27 One of the major problems in salicylate research, however, is that salicylic acid affects many different biological systems when it is present at concentrations of mmol/l—concentrations much above those normally found in patients taking low-dose aspirin.28 Our understanding of the actions of aspirin and salicylic acid is not necessarily enhanced by studies involving such concentrations.
In a broader context, dietary salicylates, like aspirin, may have benefits in regard to other ‘inflammatory’ pathologies in which the COX-2 gene is induced. COX-2 gene induction occurs in some oesophageal and gastric cancers,29,30 as well as in monocytes, macrophages and fibroblasts,31 cells which are involved in atherosclerosis, now recognized as a chronic inflammatory disease.32 However, the evidence for the putative anti-inflammatory effects of aspirin in these conditions is less well established. In fact, it is possible that inhibition of COX-2 in cases of congestive cardiac failure may have deleterious effects.31
Any hypothesis which purports to explain how a particular component of our diet helps reduce the risk of colorectal cancer, must include recognition of its limitations, as well as its strengths. Serum concentrations of salicylic acid after aspirin administration are higher than those observed in people not taking salicylate drugs. This suggests that, even if the chemopreventive action of aspirin is mainly dependent on the formation of salicylic acid, dietary salicylates may reduce the risk of colorectal cancer much less than aspirin. No one as yet knows what dose of aspirin (or salicylic acid) is required to produce chemoprevention of cancer.33 Aspirin at a dose of 81 mg was found to reduce colorectal prostaglandin concentrations or formation in two studies14,34 but not in another.35 In these and another study,36 examination of the baseline tissue prostaglandin E2 concentrations before aspirin administration reveals great variability.14,34–36 Some of the variability in tissue prostaglandin concentrations may be due to exposure to different endogenous salicylic acid concentrations, with the so-called baseline possibly reflecting salicylic acid concentration as well as other influences. There has been one randomized trial of aspirin (American Physicians Study) which reported no difference in colorectal cancer incidence between aspirin (325 mg on alternate days) and placebo.37 This trial, however, was primarily designed to examine the effect of aspirin on cardiovascular disease and involved only a 5-year period of continuous use, with follow-up for 12 years, periods of time which may have been insufficient to observe an effect.21
We believe that our hypothesis can be tested to establish its validity. Low serum salicylic acid concentrations should increase the risk of developing colorectal adenomas and adenocarcinomas. The administration of small doses of salicylic acid should be investigated to determine whether this compound has an effect on COX-2 gene transcription or any other anti-inflammatory effect. Serum or urine measurements of salicylates would be better undertaken than dietary intakes in such studies, since there is significant variability between individuals in the metabolism and excretion of salicylic acid. In addition, there may be variability in the salicylate content of dietary plants, determined in part through their differing exposure to pathogen attack. Assessment of diet also needs to incorporate an examination of the different types of plant foods, such as spices and herbs.
Our basic hypothesis is that the chemopreventive action of aspirin is due primarily to its principal metabolite, salicylic acid, and dietary salicylates can have the same effect (Figure 1
). It is also eminently possible that natural salicylates contribute to the other recognized benefits of a healthy diet.
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Acknowledgments |
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We thank Professor J. Little and Drs M. Murphy, M. McMahon and F. Toolis for their comments, Mr C. Murray for his assistance with the figure and Mrs V. Reid for typing the paper.
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Notes |
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Address correspondence to Dr J.R. Paterson, Department of Biochemistry, Dumfries and Galloway Royal Infirmary, Bankend Road, Dumfries DG1 4AP. e-mail: J.Paterson{at}dgri.scot.nhs.uk
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