Beyond the antioxidant: the double life of vitamin C.

When considering the history of vitamin C, and the names given to this molecule in early days, the Latin proverb nomen est omen suddenly comes to mind. Around 1920, when Casimir Funk introduced the term Vitamin C to indicate the nutritional factor necessary to prevent the pathological state known as scurvy, the nature of the active molecule was still unknown (Davies MB, Austin J, Partridge DA (1991) Vitamin C: Its chemistry and biochemistry. The Royal Society of Chemistry, Cambridge UK). Almost in the same years, Albert Szent-Giörgyi was striving to identify a new 6-carbon sugar he had obtained in crystal form from oranges, lemons, cabbage and adrenal glands. As humorously described by Szent-Giörgyi himself (Szent-Giörgyi A (1963) Lost in the twentieth century. Annu Rev Biochem 36:1-15), he intended to name this yet unknown carbohydrate "ignose". When this name was rejected by Sir Arthur Harden, editor of the Biochemical Journal, he suggested to name it "godnose", meaning that only God could know the real identity of the molecule. Obviously, also this choice was considered inappropriate by Harden, who suggested the plain name "hexuronic acid". Only later, when the structure of "hexuronic acid" had been completely elucidated, and biological tests performed by Swirbely identified this molecule as the anti-scurvy factor vitamin C, Szent-Giörgyi and Walter Norman Haworth decided to eventually name it ascorbic acid (Szent-Giörgyi A (1963) Lost in the twentieth century. Annu Rev Biochem 36:1-15). "Ascorbic" literally means "against scurvy", and scurvy is known to be mainly due to the inactivation of some important dioxygenases involved in the synthesis of a few key molecules, including different collagen forms (De Tullio MC (2004) How does ascorbic acid prevent scurvy? A survey of the nonantioxidant functions of vitamin C. In: Asard H, May J, Smirnoff N (eds) Vitamin C, its functions and biochemistry in animals and plants. Bios Scientific Publishers, Oxford, UK, pp. 159-172). All this has very little to do with the celebrated role of ascorbic acid (ASC) as an antioxidant. So, if the fate of ASC had to be found in its name, its role in the prevention of scurvy (i.e. beyond the antioxidant function) should be considered its main feature. But, in spite of more than 80 years of extensive research (34,424 hits in a PubMed query on January 6 2007), an unprecedented popularity among the general public, an estimated market of several billion dollars (Hancock RD, Viola R (2005) Improving the nutritional value of crops through enhancement of l-ascorbic acid (vitamin C) content: Rationale and biotechnological opportunities. J Agr Food Chem 53:5248-5257), we should honestly conclude that the fate of vitamin C is still in the first name it received, many years ago: we still ignore much of its actual relevance in cell metabolism, although we are progressively getting aware of the many facets of this fascinating molecule, and its direct involvement in the regulation of apparently unrelated pathways (Arrigoni O, De Tullio MC (2002) Ascorbic acid, much more than just an antioxidant. Biochim Biophys Acta 1569:1-9; De Tullio MC, Arrigoni O (2004) Hopes, disillusions and more hopes from vitamin C. Cell Mol Life Sci 61:209-219; Duarte TL, Lunec J (2005) When is an antioxidant not an antioxidant? A review of novel actions and reactions of vitamin C. Free Rad Res 39:671-686). Recent data on ASC involvement in cell signalling and gene expression open new perspectives, that will be presented and discussed in this chapter.