Exogenous Antigenotoxins

Exogenous antigenotoxins can be divided into synthetic and naturally occurring substances present in food or food constituents or additives.

Synthetic Antigenotoxins

Most antigenotoxins are taken up via consumption of food, and more especially from fruit and vegetables as part of the diet. Recently however, synthetic antigenotoxins such as nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin, indomethacin, sulindac and oltipraz have been recognized. Also food supplements in the form of tablets containing vitamins, minerals, trace elements and other additives can be included in this group. NSAIDs have been shown to prevent the growth and formation of colon adenomas or carcinomas in several epidemiological and intervention studies. The mechanism of this protective effect may be very complex and multifactorial but enhancement of detoxification enzymes by NSAIDs was evident. Oltipraz, which is both an inhibitor of activating systems and an enhancer of detoxification enzymes, was shown to have strong antigenotoxic potential by preventing aflatoxin Brinduced DNA damage (Figure 1). Aflatoxin B1 is a fungal toxin, thought to be the cause of many liver cancers in China and other parts of the world.

Naturally Occurring Antigenotoxins from Food

From epidemiological studies it has now been firmly established that individuals who consume diets rich in fruits and vegetables have a reduced cancer risk (Steinmetz and Potter, 1991). Many chemical substances from fruits and vegetables with antigenotoxic or antimutagenic properties have been identified, but the bulk of the potential anticarcinogens from these sources remain to be identified. Since the mechanism of most of these food-derived anticarcinogens is not known in detail, it cannot be clearly established which compound has purely antigenotoxic properties or is an otherwise cancer-preventive compound, such as a stimulator of apoptosis, inhibitor of cell proliferation, inhibitor of metastasis, etc.

Antigenotoxins from fruit and vegetables can be divided into vitamins, minerals and trace elements, and other compounds based on their putative working mechanism.

Vitamins (see Odin, 1997)

Several vitamins have been shown to have antigenotoxic potential, including vitamins A, C, E, B2, B6, B11 and B12.

Vitamin A (retinol) and its related structures are constituents of many orange- and red-coloured fruits and vegetables. They have shown antigenotoxic properties in many different test systems and experiments, mainly owing to their free radical scavenging properties. However,

Aflatoxin Biosynthesis Pathway
Figure 1 Effect of oltipraz on the metabolism of aflatoxin Bi.

it should be mentioned that vitamin A and other retinoids appear to have genotoxic properties, as was shown in some test systems. In addition, high doses of vitamin A may be toxic owing to hepatic storage, and these latter properties may possibly explain the disappointing results so far in cancer chemoprevention trials using high doses of this vitamin (see the chapter Intervention and Chemopreven-tion of Cancer).

Vitamin C or ascorbic acid is also a constituent of many fruits and vegetables. In analogy with vitamin A, the anti-genotoxic properties of vitamin C are mainly due to the scavenging of radicals, and high concentrations have also been to have mutagenic properties in some test systems. It is now generally accepted that this water-soluble vitamin is beneficial unless very high doses (up to 10 g daily) are consumed.

Vitamin E. The fat-soluble vitamin E is a naturally occurring mixture of several tocol derivatives among which a-tocopherol is the most biologically active. The basic function of vitamin E in all living organisms is as an anti-oxidant in protection against oxidative damage of hydro-phobic molecules or structures, generated either by free radicals or by radical-inducing radiation. Thus, by preventing radical-induced damage, vitamin E was shown to be an antimutagen or antigenotoxin in many experimental studies.

Folic acid or vitamin Bn. Dietary factors which directly influence methyl group availability, in particular folic acid and the essential amino acid methionine, may also be associated with cancer incidence. Folic acid, which is a component of many green vegetables such as beans, spinach and Brussels sprouts, appears to be an important antigenotoxin. Several epidemiological studies have shown that people consuming large amounts of folic acid are better protected against cancer of the colon and possibly also of the smoking-related cancers of the lungs, head and neck area than people with a low intake (Glynn and Albanes, 1994). Folic acid is an essential factor in a number of critical pathways in the cell that involves the transfer of one-carbon groups, such as methyl groups, e.g. in the biosynthesis of DNA building blocks. In this way folic acid plays a key role in DNA replication and cell division and sufficient levels of folate do prevent mutations in DNA and thus may prevent cancer.

Vitamin B2 or riboflavin has been shown to prevent binding of metabolically activated and highly carcinogenic aflatoxins to DNA. It also inhibits the damaging or muta-genic effects of irradiation or cigarette smoke condensate in in vitro test systems.

Vitamins Bg and Bi2 have an important role in the conversion of homocysteine into methionine and in other steps of the folate metabolism pathway, ultimately leading to an optimal supply of methyl groups, which is essential for prevention of DNA damage.

Minerals and Trace Elements

Minerals such as calcium and phosphorus and trace elements such as zinc, selenium and molybdenum have important functions in the synthesis of biomolecules and tissue structures, and are essential in numerous cellular and enzymatic processes. Antigenotoxic properties of these minerals and trace elements have attracted little attention. In many studies, however, deficiencies of the trace element selenium have been associated with an increased cancer risk. Since selenium is an essential component of the selenium-dependent glutathione peroxidases, which detoxify highly reactive peroxides and thus may prevent oxidation and damage to DNA, it may be considered an antigenotoxin.

Other Compounds

Most antigenotoxins cannot be categorized into the above-mentioned groups. Several hundred agents have been identified as anticarcinogens with potential antigeno-toxic properties, mainly based on data derived from one of the following study categories: (1) basic mechanism; (2) observational studies in laboratory animals; (3) studies in humans; and (4) selective screening systems. With the exception of antipromoter, antiprogression or tumour cell-killing activity, most anticarcinogens are antigenotoxins.

Apart from vitamins and trace elements, plant foods such as fruits, vegetables and cereals contain many bioactive compounds with antigenotoxic properties. Since these constituents do not belong to the classes of proteins, fats or carbohydrates, they are often called non-nutrients, microconstituents, phytochemicals or phytoprotectants. Exogenous antigenotoxins of plant origin can be roughly categorized as follows:

• Sulfides present in the allium vegetables which include onions, garlic and chives.

• Dithiolthiones, which are also sulfur-containing compounds of a more complex structure, are found in cruciferous vegetables such as cauliflower, cabbage and Brussels sprouts.

• Glucosinolates are also found in cruciferous vegetables. During cooking and chewing these glucosinolates are converted into the bioactive metabolites isothiocyanates and indoles.

• Terpenoids such as (+)-limonene, which are components of citrus fruits.

• Phyto-oestrogens including isoflavones and lignans. Isoflavones are found in cereals and pulses such as soy bean. The main dietary sources oflignans are wholegrain products, seeds, fruits and berries.

• Flavonoids such as quercetin, kaempferol, rutin, tangeritin and myricetin are widely distributed in fruits and vegetables. Rich sources are berries, potatoes, tomatoes, onions, broccoli, beans and citrus fruits.

• Other phenols and polyphenols, such as ellagic acid, caffeic acid, ferulic acid, resveratrol are found in nuts, fruits, wine and tea.

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