A role for milk proteins and their peptides in cancer prevention.

A role for the amount and type of dietary protein in the etiology of cancer has not been studied extensively. Nevertheless, there is no compelling evidence from epidemiological studies to indicate that protein, at levels usually consumed, is a risk factor for cancer. On the other hand, animal studies suggest that certain peptides and amino acids derived from dietary proteins may influence carcinogenesis. The predominant protein in milk, casein, its peptides, but not liberated amino acids, have antimutagenic properties. Animal models, usually for colon and mammary tumorigenesis, nearly always show that whey protein is superior to other dietary proteins for suppression of tumour development. This benefit is attributed to its high content of cystine/cysteine and gamma-glutamylcyst(e)ine dipeptides, which are efficient substrates for the synthesis of glutathione. Glutathione is an ubiquitous cellular antioxidant that directly or through its associated enzymes destroys reactive oxygen species, detoxifies carcinogens, maintains proteins in a reduced state and ensures a competent immune system. Various experiments showed that tumour prevention by dietary whey protein was accompanied by increased glutathione levels in serum and tissues as well as enhanced splenic lymphocyte proliferation, phagocytosis and natural killer, T helper and cytotoxic T cell activity. Whey protein components, beta-lactoglobulin, alpha-lactalbumin and serum albumin were studied infrequently, but results suggest they have anticancer potential. The minor component lactoferrin has received the most attention; it inhibits intestinal tumours and perhaps tumours at other sites. Lactoferrin acts by induction of apoptosis, inhibition of angiogenesis, modulation of carcinogen metabolising enzymes and perhaps acting as an iron scavenger. Supplementing cows with selenium increases the content of selenoproteins in milk, which on isolation inhibited colon tumorigenesis in rats.

Conjugated linoleic acid and other anticarcinogenic agents of bovine milk fat.

Prevention is an important strategy for conquering cancer. Milk fat contains a number of components, such as conjugated linoleic acid, sphingomyelin, butyric acid, ether lipids, beta-carotene, and vitamins A and D that have anticancer potential. Conjugated linoleic acid inhibits the growth of a number of human cancer cell lines and suppresses chemically-induced tumor development at a number of sites in animal models. As little as 0.1% of dietary conjugated linoleic acid inhibits the development of rat mammary tumors, independent of the amount and type of fat in the diet. Sphingomyelin, through its metabolites ceramide and sphingosine, participates in multiple antiproliferative pathways associated with suppression of carcinogenesis. Dietary sphingomyelin inhibits murine colon tumor development. Butyric acid, uniquely present in ruminant milk, is a potent antineoplastic agent and may ameliorate its potency through synergy with other milk fat components. Dietary butyric acid inhibits mammary carcinoma development in rats. In humans, ether lipids, beta-carotene, and vitamins A and D are associated with anticancer effects. Cows have the ability to extract anticarcinogenic components from pasture and feed and transfer them to milk. Use of genetic engineering and other techniques to increase the range and level of anticarcinogens in pasture and supplements may increase the anticancer potential of milk.

The French paradox unmasked: the role of folate.

The French paradox relates to the paradoxical association of a diet high in saturated fat and cholesterol with low coronary heart disease mortality and is contrary to the 'lipid hypothesis'. France and other regions with low heart disease mortality have a high consumption of fruit and vegetables. Epidemiologic studies show fruit and vegetable consumption is inversely related to coronary heart disease mortality, but recent intervention studies do not support the theory that protection is due to antioxidant vitamins. Fruit and vegetables, however, are rich sources of folate. Folate lowers plasma homocysteine levels. Even mild to moderate elevation in plasma homocysteine level is a strong risk factor for arteriosclerosis of the coronary, cerebral, and peripheral arteries. This should explain not only the French paradox but also why known risk factors may explain as little as 25% of the risk for coronary heart disease.

Cows' milk fat components as potential anticarcinogenic agents.

The optimum approach to conquering cancer is prevention. Although the human diet contains components which promote cancer, it also contains components with the potential to prevent it. Recent research shows that milk fat contains a number of potential anticarcinogenic components including conjugated linoleic acid, sphingomyelin, butyric acid and ether lipids. Conjugated linoleic acid inhibited proliferation of human malignant melanoma, colorectal, breast and lung cancer cell lines. In animals, it reduced the incidence of chemically induced mouse epidermal tumors, mouse forestomach neoplasia and aberrant crypt foci in the rat colon. In a number of studies, conjugated linoleic acid, at near-physiological concentrations, inhibited mammary tumorigenesis independently of the amount and type of fat in the diet. In vitro studies showed that the milk phospholipid, sphingomyelin, through its biologically active metabolites ceramide and sphingosine, participates in three major antiproliferative pathways influencing oncogenesis, namely, inhibition of cell growth, and induction of differentiation and apoptosis. Mice fed sphingomyelin had fewer colon tumors and aberrant crypt foci than control animals. About one third of all milk triacylglycerols contain one molecule of butyric acid, a potent inhibitor of proliferation and inducer of differentiation and apoptosis in a wide range of neoplastic cell lines. Although butyrate produced by colonic fermentation is considered important for colon cancer protection, an animal study suggests dietary butyrate may inhibit mammary tumorigenesis. The dairy cow also has the ability to extract other potential anticarcinogenic agents such as beta-carotene, beta-ionone and gossypol from its feed and transfer them to milk. Animal studies comparing the tumorigenic potential of milk fat or butter with linoleic acid-rich vegetable oils or margarines are reviewed. They clearly show less tumor development with dairy products.

Relationship between fatty acid composition and triglyceride structure of bovine milk fat.

Fourteen samples of milk fat, representing a wide range of individual fatty acid contents, were subjected to stereospecific analysis to determine fatty acid contents at the sn-1-, sn-2- and sn-3-positions of the triglycerides. Highly significant linear relationships were found between the content of a fatty acid at the 3 positions and the content of the same acid in the intact triglycerides. As the content of an acid increased in the triglycerides there were increases in the content of that acid at the 3 positions. When the content of an acid changed in the triglycerides, the content at the 3 stereospecific positions did not change at the same rate. The positions with the highest slope values corresponded to the positions where the individual fatty acids were preferentially esterified.

A comparison of the positional distribution of fatty acids in milk triglycerides of the extant monotremes platypus (Ornithorhynchus anatinus) and echidna (Tachyglossus aculeatus).

Milk triglycerides from the platypus were subjected to fatty acid and stereospecific analysis to determine the positional distribution of fatty acids in the triglycerides. Of the major fatty acids, 12∶0 was preferentially esterified at thesn-3 position, 14∶0 and 16∶0 were selectively associated with thesn-2 position, and 18∶0 was located predominantly at thesn-1 position. The unsaturated fatty acids, 14∶1, 16∶1, 18∶1, 18∶2 and 18∶3, were preferentially esterified at thesn-3 position. The fatty acid distribution pattern of the platypus, a monotreme, is similar to that of marsupials and eutherians but is in contrast to the only other extant monotreme, the echidna.

Positional distribution of fatty acids in triglycerides from milk of several species of mammals.

Milk triglycerides from the echidna, koala, Tammar wallaby, guinea pig, dog, cat, Weddell seal, horse, pig and cow were subjected to fatty acid and stereospecific analysis to determine the positional distribution of the fatty acids in the triglycerides. The samples presented a wide range of fatty acids, most of which varied in content among species. The compositions of the acids at the 3 positions also varied among species, reflecting the content of these acids in the triglycerides. However, there was a general similarity in fatty acid positional distribution patterns for all the species with the exception of the echidna. The echidna exhibited a completely different fatty acid positional distribution pattern. The saturated acids were preferentialy esterified at the sn-1-position whereas the unsaturated acids were selectively esterified at the sn-2-position. The triglyceride carbon number distribution of milk from the above species (with the exception of the Weddell seal) was determined by gas liquid chromatography and compared to that predicted by the 1-random-2-random-3-random fatty acid distribution hypothesis. Agreement was excellent between observed and predicted composition for echidna, koala, Tammar wallaby, guinea pig and pig milk, and agreement was reasonable for dog, cat, horse and cow milk. Results are discussed in relation to biochemical mechanisms.

Positional distribution of fatty acids in the triglyceride classes of milk fat.

A sample of milk fat was fractionated into high, medium and low molecular weight triglycerides by silicic acid column chromatography. Each fraction was further separated by silver ion adsorption thin-layer chromatography into triglyceride class which were subjected to stereospecific analysis. Trans-monoene fatty acids were incorporated into triglycerides in the same manner as their cis-isomer. The specific positional distribution for fatty acids in intact mild fat triglycerides was not always maintained in the molecular weight fractions or in the various classes of unsaturation. The significance of these findings is discussed in relation to biosynthetic mechanisms for milk fat synthesis.

Distribution of isomeric octadecenoic fatty acids in milk fat.

Milk fat octadecenoic acids were isolated by preparative gas-liquid chromatography of their methyl esters and separated into cis and trans isomers by argentation thin-layer chromatography. The distribution of the double bonds in the two fractions was determined by reductive ozonolysis. Cis octadecenoic acids had double bonds in positions 6 to 14. The cis-9 isomer was the most abundant isomer representing approximately 95% of the total. Trans octadecenoic acids had double bonds in positions 6 to 16, the predominant isomer being trans-11 octadecenoic acid. Data illustrating the range of variation in the distribution of positional isomers of octadecenoic acid for herd milk fat and butter are presented. There was no obvious seasonal variation in the distribution pattern. Fat from perirenal and subcutaneous adipose tissue of a dairy cow had composition similar to that of butter samples.