Phytoestrogens as natural prodrugs in cancer prevention: dietary flavonoids

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 compounds, 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 chemopreventive 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 metabolically 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 methoxylated 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.     

Phytoestrogens as natural prodrugs in cancer prevention: a novel concept

It has been generally accepted that regular consumption of fresh fruits and vegetables is linked with a relatively low incidence of cancers (e.g. breast, cervix, and colon). A number of plant-derived compounds have been identified that are considered to play a role in cancer prevention. However, at present there is no satisfactory explanation for the cancer preventative properties of the above-mentioned compound groups. The current review is an effort to develop a consistent and unambiguous model that explains how some plant-derived compounds can prevent tumour development. The model is based on recent discoveries in the fields of genomics and drug-metabolism; notably, the discovery that CYP1 genes are highly expressed in developing tumour cells but not in the surrounding tissue, and that a variety of plant-derived compounds are substrates for the CYP1 enzymes. Our hypothesis is that some dietary compounds act as prodrugs, i.e. compounds with little or no biological effect as such, but become pharmaceutically effective when activated. More specifically, we state that the abovementioned prodrugs are only activated in CYP1-expressing cells—i.e. cells in the early stages of tumour development—to be converted into compounds which inhibit cell growth. Thus, the prodrugs selectively kill precancerous cells early in tumour development. The review focuses on the identification of naturally-occurring prodrugs that are activated by the tumour-specific CYP1 enzymes and aims to assess their role in cancer prevention.     

Phytoestrogens as natural prodrugs in cancer prevention: towards a mechanistic model

It has been widely acknowledged that regular consumption of fresh fruits and vegetables is linked with a relatively low incidence of cancers (e.g. breast, cervix, and colon). Notably, dietary polyphenolic compounds that show some structural similarity to human estrogen, e.g. isoflavones, coumestans, lignans, flavones, have been proposed to play a role in cancer prevention. However, at present there is no satisfactory explanation for the cancer preventative properties of this group of compounds. Whereas polyphenolic compounds have been shown to inhibit proliferation of tumour cells in vitro, the results of in vivo tests have mostly been disappointing in this respect. It seems that mammalian phase II detoxification mechanisms make that dietary polyphenols are rapidly and effectively removed from the body, i.e. their concentration in the blood plasma hardly ever reaches levels high enough to have a possible effect on tumour growth. The polymethoxyflavones nobiletin and tangeretin, common constituents of Citrus peel, are better absorbed than polyhydroxy flavonoids, and maintain their biological activity for a longer period of time. The compounds are known to be substrates for the estrogen-converting cytochrome P450 enzymes CYP1A1 and CYP1B1, which are typically over-expressed in a range of tumour tissues. The enzymes catalyse regioselective hydroxylation and dealkylation of the polymethoxyflavones, resulting in reaction products that appear to inhibit cell proliferation via interference with the MAPK/ERK cell signalling pathway.