Phytoestrogens as natural prodrugs in cancer prevention: dietary flavonoids Randolph R. J. Arroo Æ Vasilis Androutsopoulos Æ Kenneth Beresford Æ Ketan Ruparelia Æ Somchaiya Surichan Æ Nicola Wilsher Æ Gerry A. Potter Received: 5 January 2009 / Accepted: 18 March 2009 / Published online: 9 April 2009 Ó Springer Science+Business Media B.V. 2009 Abstract There are many reasons why vegetables and fruits may protect against cancer. As well as containing vitamins and minerals, which help keep the body healthy and strengthen the immune system, they are also good sources of biologically active com- pounds, which can help to protect cells in the body from damage that can lead to cancer. Notably, dietary flavonoids and other polyphenols are thought to have an important role as chemopreventive agents. Most studies on the possible mechanism of the chemopre- ventive action of dietary compounds have assumed that free hydroxyl groups of flavonoids and other polyphenols are necessary for their biological effects. However, in the human body dietary polyphenols are rapidly conjugated by glucuronosyltransferases and sulfotransferases, two enzymes that are abundantly present in the small intestine and liver, through which all of the oral dose must pass. Thus, most polyphenols that have been studied, e.g. quercetin, kaempferol, diosmetin, and resveratrol, would not be expected to reach internal organs beyond sites directly along the gastrointestinal tract. When the hydroxyl groups in polyphenols are methylated, the resulting compounds are much less prone to glucuronidation and sulfation. Thus methoxylated compounds are more metaboli- cally stable, increasing their bioavailablity. The peel of various Citrus species can contain high concentrations of polymethoxyflavones, whereas the juice mainly contains hydroxylated flavones. At present, very little is known about the mechanisms by which methoxy- lated flavones may affect growth and development of tumour cells. Recently, it was shown that tumour specific enzymes can catalyze the O-demethylation of methoxylated flavones, resulting in the formation of flavones with free hydroxyl groups. We propose that demethylation of methoxylated flavones is another example of bioactivation of naturally occurring prodrugs. Keywords Cancer prevention Á CYP1 Á Flavonoids Á Metabolism The role of diet in prevention of cancer It has been over a quarter of a century now since the publication of Ames’ seminal review in Science on dietary carcinogens and anticarcinogens (Ames 1983). The paper has remained influential—it has been cited well over 2000 times, of which roughly 50 times in the year 2008 alone. The paper particularly emphasized the role that oxygen radicals may play as initiators of DNA damage and mutation, and thus of carcinogenesis. R. R. J. Arroo (&) Á V. Androutsopoulos Á K. Beresford Á K. Ruparelia Á S. Surichan Á N. Wilsher Á G. A. Potter Leicester School of Pharmacy, De Montfort University, The Gateway, Leicester LE1 9BH, UK e-mail: rrjarroo@dmu.ac.uk 123 Phytochem Rev (2009) 8:375–386 DOI 10.1007/s11101-009-9128-6