On the Origin of Western Diet Pathologies

Transcription

1 1 On the Origin of Western Diet Pathologies John V. Schloss 1 1 Department of Pharmaceutical Sciences, College of Pharmacy, University of New England, Portland, ME The ratio of the two sulfur-containing amino acids, methionine (Met) and cysteine (Cys), may be a determining factor for which foods contribute to longevity and health. It is shown here that substantially more Met than Cys is consistently found in foods, such as dairy and meat products, thought to contribute to pathologies associated with the Western Diet. The milk protein casein promotes cancer in animal studies. When casein comprises 20% of total dietary calories (high protein diet), it dramatically increases the risk of chemically- or virally-induced cancers 1. However, when casein comprises 5% of the diet (low protein diet), it does not have the same cancer-promoting effect. Soy protein or wheat gluten does not have the same cancer-promoting effect, even when either one comprises 20% of the diet 1. Comparison of the amino acid compositions of casein, soy protein, and wheat gluten indicates that the relative amounts of Met and Cys are responsible for the differences in the cancer-promoting effects of high-casein and other diets in animals. Casein 2 contains substantially more Met and less Cys than soy 2 or wheat gluten 3 (Table 1). To account for the differences in the cancer promoting effects of these proteins a four-fold difference in composition or greater is expected (i.e., 5 vs. 20% dietary casein). The Met/Cys ratio is the major difference in the amino acid compositions of casein, soy, and wheat gluten (6- to 10-fold). The absolute amounts of Met (two-fold difference) or Cys (3- to 5-fold difference) alone do not appear to be sufficient to explain the different cancer-promoting effects. None of the other amino acids that comprise these proteins differ to the same extent, nor are there

2 2 consistent differences between soy, gluten and casein with respect to other constituent amino acids. While suggestive, animal-feeding studies may not accurately reflect the health consequences of diet composition in humans. Milk from ruminant animals 4 has a much higher Met and lower Cys content [Met/Cys = 3-4.3] than human 4 milk [Met/Cys = 0.81]. It could be argued that the Met/Cys ratio observed in human human milk has been selected for optimal neonatal nutrition. Based on epidemiological studies 1, a diet high in animal proteins contributes to various pathologies, such as cancer, heart disease, diabetes, and osteoporosis. Dairy and meat products have higher Met/Cys ratios (Fig. 1), than legumes, grains, fruits, and vegetables 5. Diets high in animal proteins, but not diets high in plant proteins, have been reported to correlate with an increased risk of osteoporosis 6. Milk and cheese in particular have exceptionally high ratios of Met/Cys. While the absolute amount of Met is nearly equivalent for cheese and soy, the amount of Cys is 7-fold greater in soy than in cheese (Table 2). In a 12-year prospective study, milk consumption not only failed to decrease the risk of hip fracture, but increased the fracture risk slightly (1.45-fold) 7. This observation is consistent with reports that Metderived homocysteine (Hcy) can adversely affect the quality of bone collagen and increase the risk of fracture even when adequate calcium intake maintains bone density 8. Met and Cys are inextricably linked by the transsulfuration metabolic pathway (Fig. 2). Met can be converted to Cys via the transsulfuration pathway, but Cys cannot be converted to Met. Dietary studies have focused primarily on Met and Met-derived Hcy. The absolute amounts of dietary Met and Met-derived Hcy have been linked to lifespan and age-related pathologies. Met restriction extends lifespan in Drosophila and rodents without caloric restriction 9. Met restriction selectively blocks cancer proliferation in humans Met-derived Hcy promotes atherosclerosis 12. Hcy is also

3 3 implicated in cancer 13, diabetic neuropathy 14, open-angle glaucoma 15, and osteoporosis 16. The pathologies associated with the transsulfuration pathway are likely to be mediated in part through a common mechanism. Hcy and its oxidation products activate glutamate receptors, which are tied to pathologies of the central nervous system 17. Glutamate receptors are also present in other cell types, such as pancreatic islet cells, kidney, heart, bone, lymphocyte, and skin cells 18. The wide distribution of glutamate receptors offers a potential explanation for the diverse pathologies associated with transsulfuration pathway dysfunction. The most common reason for inherited homocystinuria is a deficiency in the enzyme responsible for converting Hcy to cystathionine (Fig. 2) 12. Deficiencies of the transsulfuration enzymes (Fig. 2) or nutritional deficiencies for the necessary cofactors (folic acid, B 6, or B 12 ) can lead to hyperhomocysteinemia and resultant pathologies. Depending on the relative amounts of Met and Cys in the diet, elevated Hcy can also be associated with depressed levels of Cys and Cys-dependent products, in particular glutathione and taurine. Glutathione and Hcy would have competing effects on glutamate receptors, such that depression of Cys would exacerbate the pathologies associated with hyperhomocysteinemia (Fig. 2). If Met-derived Hcy is responsible for age-related diseases, then dietary Cys supplementation should offset disease progression. Dietary Cys, provided as N-acetyl cysteine (NAC), can lower blood levels of Hcy 19. NAC has been reported to increase HDL-cholesterol 20 ; improve insulin sensitivity in patients with polycystic ovary syndrome 21 ; reduce the risk of cancer 22 ; reduce atherosclerosis in apolipoprotein E- deficient mice 23 ; increase immune function in HIV + patients 24, and slow bone resorption in post-menopausal women 25. When examining the relationship between various pathologies and diet, the effects of NAC supplementation suggest that the ratio of Met and Cys be given special attention, rather than considering absolute amounts of each

4 4 alone. Balancing the relative amounts of the two sulfur-containing amino acids in the diet may help to prevent age-related diseases. 1. Campbell, T. C. Dietary protein, growth factors, and cancer. Am. J. Clin. Nutr. 85, 1667 (2007). 2. Rutherfurd, S. M. & Moughan P. J. The digestible amino acid composition of several milk proteins: application of a new bioassay. J. Dairy Sci. 81, (1998). 3. Rombouts, I. et al. Wheat gluten amino acid composition analysis by highperformance anion-exchange chromatography with integrated pulsed amperometric detection. J. Chromatogr. A 1216, (2009). 4. Davis, T. A. et al. Amino acid composition of human milk is not unique. J. Nutr. 124, (1994). 5. FAO, A report of FAO/UN Joint Committee: Rome, Italy, P-84 (1981). 6. Feskanich, D., Willett, W. C., Stampfer, M. J. & Colditz, G. A. Protein consumption and bone fractures in women. Am. J. Epidemiol. 143, (1996). 7. Feskanich, D., Willett, W. C., Stampfer, M. J. & Colditz, G. A. Milk, dietary calcium, and bone fractures in women: a 12-year prospective study. Am. J. Public Health 87, (1997). 8. Blouin, S. et al. Bone matrix quality and plasma homocysteine levels. Bone 44, (2009). 9. Grandison, R. C., Piper, M. D. & Partridge, L. Amino-acid imbalance explains lifespan by dietary restriction in Drosophila. Nature 462, (2009).

5 5 10. Durando, X. et al. Dietary methionine restriction with FOLFOX regimen as first line therapy of metastatic colorectal cancer: a feasibility study. Oncology 78, (2010). 11. Epner, D. E. Can dietary methionine restriction increase the effectiveness of chemotherapy in treatment of advanced cancer? J. Am. Col. Nutr. 20, 443S-449S (2001). 12. McCully, K. S. Homocysteine, vitamins, and vascular disease prevention. Am. J. Clin. Nutr. 86, 1563S-1563S (2007). 13. Ferroni, P. et al. Determinants of homocysteine levels in colorectal and breast cancer patients. Anticancer Res. 29, (2009). 14. Wile, D. J. & Toth, C. Association of metformin, elevated homocysteine, and methylmalonic acid levels and clinically worsened diabetic peripheral neuropathy. Diabetes Care 33, (2010). 15. Clement, C. I., Goldberg, I., Healey, P. R. & Graham, S. L. Plasma homocysteine, MTHFR gene mutation, and open-angle glaucoma. J. Glaucoma 18, (2009). 16. Petramala, L., Acca, M., Francucci, C. M. & D Erasmo, E. Hyperhomocysteinemia: a biochemical link between bone and cardiovascular system diseases? J. Endrocrinol. Invest. 32, (2009). 17. Shi, Q. et al. L-homocysteine sulfinic acid and other acidic homocysteine derivatives are potent and selective metabotropic glutamate receptor agonists. J. Pharmacol. Exp. Ther. 305, (2003). 18. Miglio, G., Varsaldi, F. & Lombardi, G. Human T lymphocytes express N- methyl-d-aspartate receptors functionally active in controlling T cell activation. Biochem. Biophys. Res. Commun. 338, (2005).

6 6 19. Wiklund, O. et al. N-acetylcysteine treatment lowers plasma homocysteine but not serum lipoprotein(a) levels. Atherosclerosis 119, (1996). 20. Franceschini, G., Werba, J. P., Safa, O., Gikalov, I. & Sirtori, C. R. Dose-related increase of HDL-cholesterol levels after N-acetylcysteine in man. Pharmacol. Res. 28, (1993). 21. Masha, A. et al. Prolonged treatment with N-acetylcysteine and L-arginine restores gonadal function in patients with polycystic ovary syndrome. J. Endocrinol. Invest. 32, (2009), 22. Millea, P. J. N-acetylcysteine: multiple clinical applications. Am. Fam. Physician 80, (2009). 23. Shimada, K. et al. N-acetylcysteine reduces the severity of atherosclerosis in apolipoprotein E-deficient mice by reducing superoxide production. Circ. J. 73, (2009). 24. Breitkreutz, R. et al. Improvement of immune functions in HIV infection by sulfur supplementation: two randomized trials. J. Mol. Med. 78, (2000). 25. Sanders, K. M., Kotowicz, M. A. & Nicholson, G. C. Potential role of the antioxidant N-acetylcysteine in slowing bone resorption in early postmenopausal women: a pilot study. Transl. Res. 150, 215 (2007).

7 1 Table 1 Comparison of casein, soy, and gluten Met Cys Met/Cys (mg/g protein) Casein Soy Gluten

8 1 Table 2 Comparison of various foods Met Cys Met/Cys (mg/100 g food) 5 Milk Cheese Beef Chicken Lamb Pork Fish Wheat Corn Oats Rye Broad bean Chickpea Soybean

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