Introduction
Meat, especially red meat is frequently regarded as an unhealthy food, mainly due to its ‘high’ fat content and its ‘reputation’ to be a cancer promoter. As a consequence, low meat intake is often recommended to avoid or minimise the risk of cancer, obesity and metabolic syndrome. However, it is not taken into account that meat is an important source for some micronutrients such as iron, selenium, vitamins A, B12 and folic acid. Some of these are not present in plants at all or have such a low bioavailability that eating only plant-derived food might lead to deficiencies. In addition, the content of fat in (red) meat has decreased over the past years, proteins are high and carbohydrates are low which contributes to a low glycaemic index that is assumed to be ‘beneficial’ with respect to obesity, development of diabetes and cancer.
Taken together, meat is an important nutrient as an essential part of a mixed diet that ensures adequate delivery of essential micronutrients and amino acids. We will show in more detail in this article that the hypothesis of an almost meat-free diet as a cancer-preventive strategy seems more and more unlikely and that the consumption of meat might have more benefits than risks.
Meat as an important source of micronutrients
Meat including liver is an important source of several micronutrients due to the fact that some of them are exclusively present in meat or their bioavailability is much higher than from plant sources.
Vitamin A and vitamin B12 occur only in meat and can hardly be compensated for by plant-derived provitamins: provitamin B12 does not exist and provitamin A, β-carotene, would have to be taken up in large amounts due to its poor conversion rate of 1:12.
Iron has a higher bioavailability when derived from meat as heme iron than plant-derived iron. Similarly folic acid has nearly 10-fold higher bioavailability from meat (especially liver) and eggs than from vegetables. Consequently a low or no intake of meat (including liver) is associated with a risk for deficiencies in selected micronutrients.
From these facts the question arises, as to whether the ‘normal’ eating population is at a risk of deficiencies or whether there are special groups at risk of a low intake of meat-derived micronutrients.
One risk group are elderly people who are generally considered at risk of developing vitamin and trace element deficiencies, especially for the vitamins A, D, E, and for folate as well as iron and calcium (Anderson, Reference Anderson2001; Bates et al., Reference Bates, Benton, Biesalski, Staehelin, Van Staveren, Stehle, Suter and Wolfram2002; Martins et al., Reference Martins, Dantas, Guiomar and Amorin2002; Viteri and Gonzalez, Reference Viteri and Gonzalez2002). The causes of this health hazard comprise quantitative and qualitative decreased food intake, reduced energy expenditure due to sedentary life style and loss of metabolic active body cell mass, and the development of chronic age-associated disorders. As the digestive and absorptive capacity of the digestive tract is well retained through ageing a decreased absorption of macronutrients seems to be the result of a disease rather than ageing itself (Black, Reference Black2001). An exception to this rule is the impaired bioavailability of dietary iron due to gastric mucosal atrophy, which is age-related and in many cases could be regarded as a disorder rather than a disease. Nevertheless, the frequently occurring atrophic gastritis in elderly, which also affects vitamin B12 absorption, should be one reason to recommend meat intake in this risk group.
Malnutrition is far more common among institutionalised and chronically hospitalised elderly subjects rather than free-living subjects in the community and the prevalence of malnutrition is associated with the severity of morbidity, functional impairments and mental state. Such deficiencies affect a broad spectrum of micronutrients, such as the B vitamins, especially B1, B6, folate and B12, vitamin C, vitamin D and E, essential fatty acids and selenium. Thiamine and folate status need special attention in this respect, as a deficiency of these nutrients is associated with depression and impaired cognition and dementia. Intervention trials with micronutrient supplementation consisting of zinc and selenium, vitamin C, β-carotene and α-tocopherol have been associated with a reduction of infectious events, probably due to the micronutrients administration rather than the supplementation of vitamins (for detailed literature cf. Biesalski (Reference Biesalski2005)).
Pregnant women are another group at risk of micronutrient deficiencies and their adequate nutrition plays an important role in the well being of mother and child and also influences the health of the offspring, not only during the intrauterine life but also during childhood and adolescence (intra-uterine or prenatal programming). While the enhanced requirements during pregnancy normally are met by dietary intake and physiological adaptive processes, the micronutrient status of vitamin D, folic acid, iron, and zinc may become compromised without supplementation (Draper et al., Reference Draper, Lewis, Malhotra and Wheeler1993; Fogelholm, Reference Finch, Doyle, Lowe, Bates, Prentice, Smithers and Clarke1999; Saletti et al., Reference Saletti, Lindgren, Johansson and Cederholm2000) especially when meat is avoided, which can be frequently seen in women of child-bearing age. Very often a healthy diet is interpreted as a meat-free diet. Folic acid supplementation is generally recommended to decrease the risk of serious birth defects (e.g. neural tube defects). Especially in multiparious women the essential fatty acid status may become impaired and this can negatively affect the neurological and cognitive development of the offspring (Lowik et al., Reference Lowik, Van den Berg, Schrijver, Odink, Wedel and Van Houten1992; Reynolds, Reference Reynolds2002).
Selected micronutrients from meat and liver
Meat and liver are excellent sources for a number of micronutrients: low-fat pork contains 1.8 mg iron, 2.6 mg zinc, pig liver contains 360 mg magnesium, 20 mg iron and 60 μg selenium per 100 g. Thus, meat and liver (100 g/day) can cover up to 50% of the recommended daily allowance (RDA) for iron, zinc, selenium, vitamins B12, B1, B2, B6, and 100% of vitamin A. Another reason to include liver in the diet is that recent results show porcine as well as bovine liver to be almost free of harmful substances like heavy metals (a former reason to avoid the uptake of liver) which are far below the allowed threshold or even below the technical detection limit (Deutsche Gesellschaft für Ernährung, 2004).
Vitamin A during foetal lung development
Vitamin A is essential for growth and development of cells and tissues. In its active form, retinoic acid, it controls the regular differentiation as a ligand for retinoic acid receptors (RAR, RXR) and is involved in the integration (gap junction formation) of cell formations (Morree, Reference Morree and Jeon Friedlander1992; Kurokowa et al., Reference Kurokowa, DiRenzo and Boehm1994). Vitamin A plays a substantial role, especially in the respiratory epithelium and the lung. During moderate vitamin-A deficiency, the incidence for diseases of the respiratory tract is considerably increased and repeated respiratory infections can be influenced therapeutically by a moderate vitamin-A supplementation (Sommer, Reference Sommer1993). Kohlhäufl et al. (Reference Kohlhäufl, Häussinger, Stanzel, Markus, Tritschler, Mühlhöfer, Morresi-Hauf, Golly, Scheuch, Jany and Biesalski2002) showed that inhalation of vitamin A for 3 months can lead to a substantial remission of lung meta- or dysplastic epithelium. In addition to the importance of this vitamin for lung function, vitamin A is also responsible for the development of many tissues and cells as well as for the embryonic lung development. Recent studies proved that the control occurs by different expressions of retinoid receptors. In fibroblast-like cells close to the alveolar cells, in type-II-cells as well as in the respiratory epithelium of the foetal lung retinyl-esters are present as local extrahepatic stores. The importance of these retinyl-esters as ‘acute reserve’ during the development of the lung becomes apparent during the late phase of gestation and the beginning of lung maturation. During this period a rapid emptying of the retinyl-ester stores in the lung of rat embryos was shown by Geevarghese and Chytil (Reference Geevarghese and Chytil1994). This depletion is the result of an increased demand in the process of the lung development, because the retinoic acid is ‘instantly’ needed for the process of cellular differentiation (e.g. proximalisation) and metabolic work (surfactant).
The prenatal lung development is also influenced by glucocorticoids. The steroid hormones have a similar effect on lung development as vitamin A, i.e. these two factors complement each other. This is not surprising, because the receptors for steroids and retinoids belong to the same multireceptor-complex. The application of dexamethasone leads to an increase of the maternal and foetal retinol-binding protein. Thus, the vitamin A-supply is improved via the regular hepatic export pathway. Such an increase of the vitamin-A concentration in the systemic circulation obviously diminishes morbidity and mortality of premature infants due to bronchopulmonal dysplasia (Shenai et al., Reference Shenai, Rush, Stahlman and Chytil1990). After administration of dexamethasone, as well as after administration of steroids, a significant reduction of retinyl-esters in the maturing lung can be detected, together with a moderate increase of retinol, the hydrolysation product of retinyl-ester. This observation may explain the therapeutical success with steroids but also their failures during the therapy of lung-distress-syndrome of premature infants. As far as an insufficient supply is concerned, inappropriate retinyl-ester stores, caused by a shortage of supply to the foetal lung during the late pregnancy can prevent the regulatory effect of glucocorticoids for the vitamin-A-metabolism of the lung cells.
Very low plasma vitamin-A levels are recurrently found in premature infants, especially in cases with lung-distress-syndrome. This can, amongst other things, be attributed to the relative immaturity of the liver for the synthesis of retinol-binding proteins. The neonate is almost exclusively dependent on the mother in its supply, this includes the lung retinyl-esters which are either absorbed by the cells directly (from chylomicrons) or by esterification of retinol after uptake into the cells. These lung retinyl-ester stores can only be sufficiently filled if the mother guarantees an appropriate vitamin-A supply especially during the late pregnancy. This can be either done by supplementation or by an appropriate intake of meat or especially liver but not by the uptake of provitamin A (β-carotene). In a recent pilot study Schulz et al. (Reference Schulz, Engel, Kreienberg and Biesalski2006) found that even in Germany in women with twins or with short birth rates there was insufficient retinol uptake and, as a consequence, low plasma levels although their β-carotene uptake was more than sufficient as were their β-carotene plasma levels.
Vitamin A in the postnatal lung
A disease seen recurrently in connection with vitamin-A supply is the bronchopulmonary dysplasia (BPD). The pathogenesis of BPD certainly depends on a multitude of factors, however some of the observed morphological changes are very similar to those seen in vitamin-A deficiency of humans and animals. In particular, there is focal loss of ciliated cells with keratinising metaplasia and necrosis of the bronchial mucosa as well as an increase of mucous secreting cells (Stofft et al., Reference Stofft, Biesalski, Zschaebitz and Weiser1992).
Especially because focal keratinising metaplasia may occur as a consequence of vitamin-A deficiency, is strengthening the assumption of an impairment of the differentiation on the level of the gene-expression. Since vitamin A regulates the expression of different cytokeratins and therefore influences the terminal differentiation, it seems obvious to suppose common mechanisms. Consequently, the premature, but especially the neonate, are dependent on a sufficient supply of vitamin A. The earlier a child is born before due date, the lower are its serum-retinol-levels (Mupanemunda et al., Reference Mupanemunda, Lee, Fraher, Koura and Chance1994). Since a further decrease of the serum-retinol-level and RBP-level occur postnatally, the plasma value at the time of birth is considered to be a critical parameter regarding the lung development.
Reduced plasma levels during the first months of life have a considerable influence on the overall development as well as on the susceptibility of infants to infections. With reduced retinol-plasma-levels, repeated infections are more often described and they are counted among the main complications of a poor vitamin-A supply in developing countries. In addition, the serum vitamin-A level during infectious diseases, particularly of the respiratory tract, continues to drop which might be explained by an increased metabolic demand and/or with an increased renal elimination of retinol and of RBP during acute infections (for literature see Biesalski (Reference Biesalski2005)).
The discussion of whether liver should be avoided as a component of a healthy diet is primarily based on questionable contaminants suspected in the liver (e.g. hormones, xenobiotics, metals etc.) which nowadays are hardly detected (see above). If β-carotene from vegetables were the only source of vitamin A, more than 500 g mixed and β-carotene rich vegetables per day would need to be eaten to reach the recommended 1 mg retinol. Concerning contaminants, it has not been evaluated whether this amount of vegetables contains more contaminants than a portion of liver, especially as their concentration in vegetables and fruits seems to have increased during the late 1990s and early 2000s (Deutsche Gesellschaft für Ernährung, 2004). Thus, a small portion of liver (100 g) twice a month is neither toxic nor teratogenic and contributes to a sufficient supply of the body with vitamin A.
Iron
Iron supports oxidative metabolism. It is essential for gas exchange at the tissue and cellular levels through haemoglobin oxygenation in red cells and myoglobin in skeletal muscle. Moreover, iron-containing enzymes are involved in cellular energy metabolism and in host-defence responses. These various roles are due to the biological catalytic activity of iron. Like many other transition elements, it possesses unfilled atomic orbitals that allow it to co-ordinate electron donors and participate in redox processes.
Iron is one of the most abundant elements in the Earth's crust, paradoxically, iron deficiency is the most common and widespread nutritional disorder in the world. Due to biological losses, such as cyclical monthly menstruation in fertile-aged women, excessive infestation with blood-feeding parasites, or poor bioavailability of iron from plant-based diets, it is estimated that as many as 4 to 5 billion people, 66 to 80% of the world's population, may be iron deficient (World Health Organisation (WHO), 1992). At any given time, 2 billion people – over 30% of the world's population – are anaemic, mainly due to iron deficiency, and in developing countries this is frequently exacerbated by malaria and worm infections (WHO, 1992).
Iron deficiency is a particular risk for women and girls of child-bearing age, because of menstrual losses. In a recent Irish food consumption survey, almost half of women aged 18 to 50 years had inadequate iron intakes when compared with national average requirements. In the British National Diet and Nutrition Survey, iron intakes were found to be low in girls (aged 7 to 18 years), with iron intakes decreasing with age. Adolescent females (15 to 18 years) were found to have extremely low intakes of iron when compared with UK dietary reference values. Depending on the composition of the individual diet the bioavailability of iron can differ 5- to 10-fold. The different bioavailability depends on the presence or absence of different ligands (phytates from cereal products, tannins from coffee and tea and oxalates from vegetables) which form complexes with iron and zinc and block their absorption. A diet which is primarily composed of vegetables, rice, beans and maize is associated with a poor iron bioavailability which at least explains the high incidence of anaemia in developing countries. Around 100 g pork meat added to the vegetarian diet described above increases the iron absorption 3.6-fold as does an even lower amount of liver.
Folate
In European countries the average folate intake in adults was found to be remarkably similar, around 300 μg/day in adult males and 250 μg/day in adult women (De Bree et al., Reference De Bree, Van Dusseldorp, Brouwer, Van het Hof and Stegers-Theunissen1997). This is slightly below the recommended intake level of 400 μg/day and even lower than that recommended for pregnant women and women planning a pregnancy. For these groups an intake of 600 μg/day is considered protective against neural tube defects (NTD), which appear around 700 times per year in Germany, and some other possible malformations (e.g. lip cleft). More than 90% of women of childbearing age have dietary folate intakes below this optimal level while an optimal level can reduce the risk to develop NTD by up to 70%. If there is an anamnestic risk for NTD, a daily uptake of 4000 μg is recommended.
The link between poor folic acid status and NTD is well documented but poorly characterised. Poor status is also linked to raised plasma homocysteine, a risk indicator for cardiovascular diseases and poor status may also increase the risk of neurological disorders and cancers. As the ‘protective’ folate levels are most important during the first 3 weeks after conception, a sufficient ‘in time’ supplementation cannot always be planned and therefore folate levels should always be in the recommended range. This might either be assured by a supplementation with folate (100% bioavailability) – in the US salt and flour are generally folate-supplemented – or again regarding the bioavailability, by an adequate uptake of liver.
Vitamin B12
Vitamin B12 is found only in animal products. In a recent UK study of 250 vegetarian and 250 vegan men, approximately one quarter of vegetarians and more than half of vegans had sub-optimal intakes of vitamin B12. Plasma vitamin B12 levels were low in the vegetarians and extremely low in the vegan group, with more than a quarter below the threshold level where neurological signs may develop (130 ng/l; Lloyd-Wright et al., 2001). The elderly are also at risk of vitamin B12 deficiency, due to physiological changes resulting in reduced absorption. In one study in the UK, vitamin B12 status in some people aged 65 and over was inadequate in both men and women even though vitamin B12 intakes were adequate when compared with UK dietary reference values (Finch et al., 1998). To assure the RDA of vitamin B12 (3 μg/day for adults), again meat (bovine 5 μg/100 g) and especially liver (depending on the species 30 to 65 μg/100 g) are the best sources.
Selenium
Selenium is often considered as belonging to the group of antioxidant nutrients, since it is incorporated into the enzyme glutathion peroxidase, which acts as a cellular protector against free radical oxidative damage. A secondary end-point analysis of a randomised placebo-controlled skin cancer prevention trial suggested that supplemental selenium might reduce the incidence of and mortality from cancers at several sites (Clark et al., Reference Clark, Combs, Turnbull, Slate, Chalker, Chow, Davis, Glover, Graham, Gross, Krongrad, Lesher, Park, Sanders, Smith and Taylor1996). However, the efficacy of selenium as a cancer-preventive agent should await the results of large on-going controlled studies. Selenium is, like many other nutrients, necessary for a well functioning immune system, and has been pointed out as particularly efficacious against HIV and AIDS. However, a systematic review found no evidence for a clinical relevant function of selenium in that respect (Ozsoy and Ernst, Reference Ozsoy and Ernst1999).
Although selenium is widely distributed in the environment, the selenium content of foods is greatly affected by soil on which crops grow or animals graze. Recent evidence suggests that selenium intakes in most parts of Europe are falling and are low when compared with recommended intakes (Rayman, Reference Rayman2000). Declining intakes in the last three decades have been attributed mainly to a change in the source of wheat for bread and cereal products, from predominantly North American to European origin (from a high to a low selenium content). These are reflected in decreasing plasma or serum selenium levels. Due to its antioxidant effects, selenium may be protective against chronic degenerative diseases. In the UK, selenium intakes were low in the majority of the elderly (aged 65 and over) in the British National Diet and Nutrition Survey when compared with UK dietary reference values (Thane and Bates, Reference Thane and Bates2001). Selenium intakes decreased with increasing age in this population subgroup.
Zinc
Zinc-deficient individuals demonstrate slower wound healing and are more prone to infections. However, studies of the effect of zinc supplementation aimed at the healing rate of venous leg ulcers have been inconclusive. A Cochrane review concluded that oral zinc did not appear to aid the healing of leg ulcers, and that there was only weak evidence for a benefit in patients with venous leg ulcers and low serum zinc (Wilkinson and Hawke, 2002). Zinc has been found to inhibit rhinovirus replication in vitro. Some studies have demonstrated that zinc may beneficially affect cold symptoms; however a meta-analysis of randomised controlled trials concluded that there is no evidence for the effectiveness of zinc in reducing the duration of common cold symptoms (Jackson et al., Reference Jackson, Lesho and Peterson2000). Finally, in settings with high rates of stunting and low plasma zinc concentrations, zinc supplementation may improve children's growth (Brown et al., Reference Brown, Peerson and Allen1998). Until now, supplementation studies did not reveal consistent results. However, a low intake of zinc is associated with a weakened immune system. T-cell-count, T-cell-proliferation and function and NK-cell activity are all reduced. Especially in elderly a reduced zinc status is evident (Lukito et al., Reference Lukito, Wattanapenpaiboon, Savige, Hutchinson and Wahlqvist2004). In the same group, a higher protein intake (together with slight exercise) stops sarkopenia, a progressive loss of lean body mass. The RDA for zinc is about 12 to 15 mg/day, during pregnancy and lactation a higher need of zinc is documented (20 to 25 mg/day) as well as during chronic inflammatory diseases (Rink and Gabriel, Reference Rink and Gabriel2000). Again, meat and liver are the best sources.
Protecting micronutrients in meat with respect to cancer
The authors are well aware that meat is under suspicion as a carcinogen, particularly if barbecued and eaten in large quantities. Also the total amount of the energy taken up by the food and its composition of proteins, fat and carbohydrates seems to be of great relevance. However, this is not part of the present consideration but can be considered in relation to other published reviews (Biesalski, Reference Biesalski2002 and Reference Biesalski2005)
Folate
It is frequently argued that the increased risk of different types of cancer resulting from low intake of fruits and vegetables is a result of a folate deficient diet, because fruits and vegetables are important sources for folate. While this is true, the bioavailability of folate from meat and liver is much better than from fruits and vegetables. Several studies have claimed that a low folate intake has been related to an increased occurrence of colon adenomas (Giovannucci et al., Reference Giovannucci, Stampfer and Colditz1993a; Benito et al., Reference Benito, Stiggelbout and Bosch1991) and cancer (Freudenheim et al., Reference Freudenheim, Graham and Marshall1991). Zhang et al. (Reference Zhang, Hunter and Hankinson1999) studied the effect of alcohol and folate on breast cancer. The increased cancer risk associated with alcohol consumption (>15 g/day) was reduced in women who consumed at least 300 μg folate per day which still is under the RDA of 400 μg/day. The major source of folate was supplements, a form which has a very good bioavailability compared with vegetable-derived folic acid. In another study, folate supplementation decreases the risk of colon cancer significantly (Giovannucci et al., Reference Giovannucci, Stampfer and Colditz1993b).
An additional aspect, also involved in methylation reactions, which might contribute to the individual colon cancer risk, is a genetic polymorphism of a key enzyme of folate metabolism: the methylenetetrahydrofolate-reductase (MTHFR). This enzyme converts 5,10- methylenetetrahydrofolate to 5- methyltetrahydrofolate, the major circulatory form of folate in the body and primary methyl donor for the methylation of homocysteine to methionine. This pathway is a critical to the methylation of DNA. As described above alterations in the methylation process can result in abnormal expression of oncogenes and tumour suppressor genes (Baylin et al., Reference Baylin, Makos and We1991). The polymorphism of the human MTHFR gene (alanine to valine substitution, coding for a thermolabile enzyme with reduced activity) results in elevated plasma homocysteine levels. Homozygous individuals have 30% normal enzyme activity, heterozygous 65%. Up to now there are controversial results in correlating this polymorphism with individual colon cancer risk. However, supplementation of folate or a diet rich in folate with optimum bioavailability (meat and liver better than vegetables and fruit) will lower homocysteine and might therefore influence the individual risk (Bronstrup et al., Reference Bronstrup, Hages, Prinz-Langenohl and Pietrzik1998).
Vitamin A
On the basis of a few reports it is assumed that a ‘local’ vitamin-A deficiency exists in meta- and dysplastic areas of the bronchial wall. Measurements of vitamin-A concentrations in metaplastic areas of the respiratory epithelium and the cervix epithelium proved that vitamin A was no longer to be found, in contrast to the surrounding healthy tissues. At the moment it is difficult to distinguish between cause and effect. Studies carried out by Edes (Reference Edes1991) and co-workers point to an induction of metaplasia caused by a vitamin-A deficit. These studies showed that a depletion of vitamin-A ester stores in different tissues is caused by toxins that are present in cigarette smoke (predominantly polyhalogenated compounds).
Epidemiological evidence supports the assumption that the development of obstructive respiratory diseases plays an important role as regards cancer mortality of smokers. It was shown that the relative risk for smokers to be affected by lung cancer, when they suffered from obstructive ventilation disorder (Skillud et al., Reference Skillud, Offord and Miller1987) was significantly higher than that of comparative groups with normal lung-function parameters.
A survey of the dietary habits within the scope of the ‘National Health and Nutritional Examination Survey’ showed that an inverse correlation (Morabia et al., Reference Morabia, Sorenson, Kumanyika, Abbey, Cohen and Chee1989) existed between chronic obstructive pulmonary diseases (COPD) and vitamin-A supply as the only one of 12 examined dietary components. COPD increases lung cancer risk significantly. If a diminished supply of vitamin A increases the appearance of obstructive respiratory diseases, a marginal or local vitamin-A deficit could be responsible for the observed changes of the respiratory mucosa. Such a deficit results in a loss of cilia, an increase of secreting cells and finally the formation of squamous metaplasia (Chytil, Reference Chytil1985; Stofft et al., Reference Stofft, Biesalski, Zschaebitz and Weiser1992). Such changes (decrease of ciliated cells with simultaneous increase of the secretion) are noted among smokers (Gouveia et al., Reference Gouveia, Mathe and Hercend1982; Mathe et al., Reference Mathe, Gouveia, Hercend, Gros, Dorval and Meyskens1983) and cause a reduction of the mucociliary clearance. This reduction of the mucociliary clearance, associated with an increased adsorption of the respiratory syncytial virus (RSV) (Donelly, Reference Donelly1996), could explain the extraordinarily high morbidity and mortality for respiratory infections of children with vitamin-A deficiency in developing countries (Sommer, Reference Sommer1993).
There is sound evidence from experimental studies that the alteration of the respiratory mucosa, caused by the vitamin-A deficiency, can be re-differentiated into its functional original epithelium, in vivo as well as in vitro, following vitamin-A supplementation (for literature cf. Biesalski (Reference Biesalski2005)). Squamous metaplasia of the bronchial mucosa, which occurs in smokers in spite of a sufficient supply with vitamin A as an effect of inhalative noxae could also be reversed through systemic application of high retinoid concentrations in vitro (Lasnitzki and Bollag, Reference Lasnitzki and Bollag1987) and in humans in vivo (Gouveia et al., Reference Gouveia, Mathe and Hercend1982; Mathe et al., Reference Mathe, Gouveia, Hercend, Gros, Dorval and Meyskens1983).
Selenium
The best known biochemical role for selenium is as part of the active site of the enzyme glutathione peroxidase (GPx). The metabolic function of this enzyme is vital for cells, as it is part of a mechanism responsible for the metabolism and detoxification of oxygen. It is assumed that GPx can protect DNA from oxidative damage and consequently from mutation leading to neoplastic transformation of cells (Combs and Clark, Reference Combs and Clark1985). At relatively high levels, selenium protects against the action of certain carcinogens in various animal models (Halliwell and Gutteridge, Reference Halliwell and Gutteridge1989). As well as in in vitro and in vivo studies, organic and inorganic selenium have been demonstrated to inhibit proliferation of normal and malignant cells and inhibit tumor growth (Redman et al., Reference Redman, Xu and Peng1997). Apoptosis may result from competition of selenium for s-adenosyl-methionine with ornithine decarboxylase (ODC). ODC acitivity is indeed critically involved in cancerogenesis. From geographical studies it is documented that in areas with sufficient selenium concentrations in the diet (depending on selenium concentrations of the soil), there is an inverse relationship between selenium status and cancer (Clark et al., Reference Clark, Cantor and Allaway1991). Epidemiological studies showed inverse associations of selenium intake or plasma levels and cancers of different sites (prostate, colon, skin etc.). In a recent, double blind, placebo controlled cancer prevention trial 200 μg selenium (approx. three times the RDA) were given daily to patients with histories of basal and squamous skin carcinoma (Clark et al., Reference Clark, Combs, Turnbull, Slate, Chalker, Chow, Davis, Glover, Graham, Gross, Krongrad, Lesher, Park, Sanders, Smith and Taylor1996). Selenium supplementation did not influence the primary endpoint prevention of recurrent skin cancers, but surprisingly was inversely associated with the incidence of and mortality from total prostate, lung and colorectal cancers. Recently Yoshizawa et al. (Reference Yoshizawa, Willet and Morris1998) reported a strong inverse association of toenail concentration of selenium and prostate cancer risk (65% reduced risk in the highest quintile). Toenail concentration reflects long-term intake of selenium with the diet and is consequently influenced by bioavailability. From intervention trials and from epidemiological studies there is now evidence indicating “that substantially increases in the consumption of selenium by men taking 80 to 90 μg/day or more may have striking impact on prostate cancer rates” (Giovannucci, Reference Giovannucci1998). Recent surveys indicate that average intake of selenium may be as low as 30 to 40 μg/day (Rayman, Reference Rayman2000). Intake data however do not really reflect the bioavailability. Consequently the diet has a strong influence on total selenium supply of tissues. Especially in areas with low soil selenium dietary sources containing substantial amounts of selenium with good bioavailability should be recommended. In the US selenium is mainly supplied by cereals, breads, meats and meat products. Beef alone is estimated to contribute approximately 17% of the total selenium in the American diet. Two recent studies in humans showed that meat was as good a source of selenium as wheat (Van der Torre et al., Reference Van der Torre, Van Dokkum and Schaafsma1991) and that l-selenomethionine (SeMet) was absorbed more rapidly than selenite in selenium deficient men (Xia et al., Reference Xia, Zhao and Zhu1992). In a recent study the bioavailability of selenium was estimated from various portions of fully cooked commercial cuts of beef, including liver, strip loin, round, shoulder and brisket in rats (Shi and Spallholz, Reference Shi and Spallholz1994). The bioavailability from the beef diets was compared with that of selenium as selenite or SeMet. Liver GPx recovery (after depletion), muscle tissue deposition and plasma levels were taken as markers of bioavailability. Liver GPx-recovery was highest from SeMet>beef muscle>selenite = beef liver. Muscle deposition was highest from SeMet>beef muscle>selenite = beef liver. From these results the authors concluded that the bioavailability of selenium from beef is higher than, or at least equal to, that of selenite and slightly lower than that of SeMet. Again one can assume, as for the other micronutrients, that meat is an important source for bioavailable selenium.
Zinc
The situation about zinc levels in cancer patients is still unclear, as some studies describe lower zinc levels in their patients (Mellow et al., Reference Mellow, Layne and Lipman1983; Rogers et al., Reference Rogers, Thomas and Davis1993), while others did not find this association (Kok et al., Reference Kok, Van Duijn and Hofman1988; Kabuto et al., Reference Kabuto, Imai and Yonezawa1994). There is good evidence that zinc may contribute to prostate cancer incidence. Total zinc levels in the prostate are 10 times higher than in other soft tissues (Mawson and Fisher, Reference Mawson and Fisher1952). Uptake of zinc via a membrane transporter into prostatic epithelial cells is under the control of hormones (testosterone, prolactin) (Costello et al., Reference Costello, Liu and Zou1999). Physiological concentrations of zinc inhibit growth of androgen sensitive and androgen-independent prostate cancer cell lines via cell cycle arrest, apoptosis and necrosis (Iguchi et al., Reference Iguchi, Hamatake and Ishida1998; Liang et al., Reference Liang, Liu and Zou1999). Epidemiological findings are not consistent and a few studies estimating the effect of supplementation on prostate cancer risk are still controversial (for review, see Platz and Helzlsouer (Reference Platz and Helzlsouer2001)). One important reason for this inconsistency might be the high variability of zinc content of different sources, especially meat and sea-food. Furthermore zinc has a much better bioavailability from meat than from vegetables and other factors, present in the diet may have additional effects: citric acid, histidine and cysteine increase, phytate and oxalate decrease the absorption of zinc (Groff and Groopper, Reference Groff and Groopper2000). Better biomarkers are required to help estimate the individual zinc status and consequently the individual risk. At present there is no clear-cut evidence for a preventive effect of zinc on prostate cancer from epidemiological studies. Some small case control studies indicate low plasma zinc or low prostatic zinc levels in patients with prostate cancer compared with healthy controls (for review see Platz and Helzlsouer (Reference Platz and Helzlsouer2001)). One factor contributing to low intake might be a decline in red meat consumption which has been reported in New Zealand, UK, USA and Canada (cf. Biesalski, Reference Biesalski2005), concomitant with an increase in intakes of unrefined cereals, nuts and legumes. Red meat is a rich source of readily available zinc, whereas cereals contain different levels of phytic acid, thus decreasing the uptake of zinc. Indeed, the recommendation to decrease or even avoid meat intake may result in a low zinc status as recently documented in women from New Zealand (Gibson et al., Reference Gibson, Heath and Limbaga2001). In a cross sectional study of 330 women, the authors assessed the interrelationship of dietary intakes, biochemical zinc status and anthropometric indices. Changes in food selection patterns (reduction of red meat) were suggested to be responsible for the lower biochemical zinc nutrition. This study is an example that a mixed and balanced diet, including meat and meat products, is the best way to ensure sufficient intake of all essential and potentially cancer preventive components.
Meat consumption, especially red meat, is not carcinogenic per se, even if it contains components that are assumed to contribute to cancer formation. On the other hand, a reduced cancer risk in persons with a high intake of fruit and vegetables is described attributing the preventive effect to protecting factors such as carotenoids, flavonoids, further phytochemicals and also folic acid, selenium, zinc and other components. Why should these compounds be less effective if they reach the body via meat? The balance of promoting and protecting factors within the diet is important for the protection against cancer. Furthermore the insulin-resistance hypothesis shows that a nutritional behaviour leading to a metabolic syndrome (high energy, high glycaemic carbohydrates) might favour colon cancer or even cancers from other sites. Willett (Reference Wilkinson and Hawke1999) gave a very good and comprehensive advice: “Current nutritional recommendations for the prevention of cancer include increased consumption of fruits and vegetables; reduced consumption of red meat and animal fat; and avoidance of excessive alcohol. For many individuals a daily multivitamin that contains folic acid may also be part of a reasonable cancer prevention strategy.” Only a reasonable amount of exercise should be added to this advice.
Conclusions
Any kind of an unbalanced diet, either avoiding meat or fruit or vegetables more or less leads to (micro-) nutrient deficiencies and consecutive disorders or diseases like metabolic syndrome and cancer, especially in groups with higher needs (pregnant or lactating women, excessive exercise, growing children, elderly, etc.). At this time one has to assume, that a mixed and balanced diet with higher amounts of fruits and vegetables and moderate amounts of meat including liver, paired with body exercise is recommended and seems to be the best recipe for nutritional support for the prevention of deficiencies and physiological malfunctions.
