Plasma ascorbic acid in heart disease

Abstract

Kay-Tee Khaw and co-workers' findings (March 3, p657)1Khaw KT Bingham S Welch A et al.Relation between plasma ascorbic acid and mortality in men and women in EPIC-Norfolk prospective study: a prospective population study.Lancet. 2001; 357: 657-663Summary Full Text Full Text PDF PubMed Scopus (447) Google Scholar contrast strikingly with the frequently disappointing, and sometimes disconcerting, results of molecularly based cancer chemoprevention trials. For example, β-carotene, admin-istered alone or together with vitamins A, E, or ascorbic acid, for the prevention of cancer in heavy smokers or asbestos workers, does not lower cancer risk (and in some cases incidence increases). These supp-lementations are, therefore, suspected of having harmful as well as beneficial effects.2Omenn GS Chemoprevention of lung cancer is proving difficult and frustrating requiring new approaches.J Natl Cancer Inst. 2000; 92: 959-960Crossref PubMed Scopus (27) Google Scholar Epidemiological data firmly linking high fruit and vegetable consumption to health benefits have prompted efforts to reproduce these effects with a single industrially derived molecule. In-vitro and in-vivo models show frequently the expected biological activity of single nutrients. The trouble comes when these do not arise after consumption in human beings.3Meagher EA Barry OP Lawson JA Rokach J FitzGerald GA Effects of vitamin E on lipid peroxidation in healthy persons.JAMA. 2001; 285: 1178-1182Crossref PubMed Scopus (259) Google Scholar Khaw and co-workers remark that benefits from ascorbic acid supplements remain to be seen. However, dietary supplementation of 500 mg ascorbic acid daily (ie, a common commercial dose) to healthy volunteers for 4–6 weeks causes substantial oxidative DNA damage in circulating lymphocytes.4Podmore ID Griffiths HR Herbert KE Mistry N Mistry P Lunec J Vitamin C exhibits pro-oxidant properties.Nature. 1998; 392: 559Crossref PubMed Scopus (709) Google Scholar The surprisingly healthy outcomes associated with an increase of just one serving per day of fruit and vegetables1Khaw KT Bingham S Welch A et al.Relation between plasma ascorbic acid and mortality in men and women in EPIC-Norfolk prospective study: a prospective population study.Lancet. 2001; 357: 657-663Summary Full Text Full Text PDF PubMed Scopus (447) Google Scholar are in keeping with the observation that whole-apple extracts exert much greater (>263-fold) total antioxidant activity and stronger inhibitory effects on growth of colon and liver cancer in vitro than does synthetic ascorbic acid, presumably because of their high content of nutrients and phyto-chemicals.5Eberhardt MV Lee CY Liu RH Antioxidant activity of fresh apples.Nature. 2000; 405: 903-904Crossref PubMed Scopus (951) Google Scholar Khaw and co-workers themselves considered the possibility that the measured plasma ascorbic acid might only be an indicator of other protective factors. They give the association of ascorbic acid with numerous other components present in foods as the most likely alternative explanation. The overall combination of substances (holistically) present in fruit and vegetables could be the true cause of the overall biological benefits of green vegetables. One 50 g serving of apple, for example, contains about 219 mg of phytochemicals, including around 145 mg phenolic compounds, 71 mg flavonoids, and 2·85 mg ascorbic acid.5Eberhardt MV Lee CY Liu RH Antioxidant activity of fresh apples.Nature. 2000; 405: 903-904Crossref PubMed Scopus (951) Google Scholar Although individually present in only small amounts, phenolics and flavonoids have a much lower LD50 (ie, the dose capable of killing half an animal population within 24 h) than ascorbic acid (<1000 vs >8000 mg/kg in rats). However, the traditionally recognised benefit of apples exemplifies how overall toxicological outcomes can depend on factors other than single (or merely cumulative) doses. In the dietary context, the multiple interactions of agonist or antagonist effects exerted by a mixture of substances might have very different biological outcomes for equimolar quantities of any of its single components. Thus, when assumed as a natural cocktail, what might otherwise be poisonous can actually be salutary. On public-health grounds, such considerations provide rational basis for the dietary promotion of plant products rather than molecularly based pills.