- Email: [email protected]
Dietary protein and hypertension:
EDITORIAL OPINIONS
Dietary Protein and Hypertension: Where Do We Stand? Despite the prevalence of high blood pressure worldwide, this disease generally commands less social awareness than do coronary artery disease and stroke. In addition, because hypertensive patients exhibit few symptoms, they are less likely to seek and obtain treatment. Moreover, compliance with traditional pharmacologic therapy is reduced by unacceptable side effects. Accordingly, there has been a renewed interest in non-pharmacologic antihypertensive therapy. Dietary manipulations are attractive as non-pharmacologic therapy because they can be instituted before diagnosis and may prevent blood pressure elevation. The Dietary Approaches to Stop Hypertension (DASH) trial demonstrated conclusively that moderate dietary manipulation could be successful as nonpharmacologic hypertension treatment. For many years, the focus of dietary intervention has been on intake of electrolytes. Indeed, the Joint National Commission reports on treatment of hypertension only briefly mention dietary protein as a potential approach to modify high blood pressure1,2 citing insufficient research in this area. Since that time, accumulating evidence (albeit sometimes contradictory) has indicated that dietary protein can influence blood pressure. A traditional view, still espoused by some today, had been that consumption of animal protein increases, whereas vegetable protein decreases, blood pressure.3 Nevertheless, there is now substantial data indicating that animal protein intake, in fact, reduces blood pressure.4,5 For example, Liu et al. used an objective measure of animal protein intake (urinary 3-methyl histidine levels) and reported a significant inverse relation between animal protein intake and blood pressure in humans.6 The recent study by Ait-Yahia et al.7 (in this issue of Nutrition) demonstrates a similar effect of dietary fish protein in a hypertensive animal model. Hypertensive patients also experience a significant decrease in blood pressure when fed a diet supplemented with fish.8 Soy protein also may have a beneficial effect on cardiovascular health. Much of the research focus has been on improvement in the plasma lipid profile.9,10 Nevertheless, it was suggested more than 25 y ago that soy foods could also attenuate hypertension.11 My colleagues and I12 and others13,14 have confirmed this effect in animals. Although findings in humans may be somewhat more equivocal, the weight of evidence has suggested that dietary soy protein also lowers blood pressure in patients.15,16 Accordingly, at the present time, animal and human observational studies support the conclusion that dietary protein, from animal, fish, or vegetable sources, can lower blood pressure in the appropriate setting. Although the antihypertensive effect of dietary protein is relatively well established, several issues require further intensive research effort. First, understanding the mechanisms underlying the blood pressure lowering effect of dietary protein is paramount. Currently, there are multiple proposed mechanisms. In the case of animal protein, it has been speculated that certain amino acids such as taurine may exert a blood pressure lowering effect,4,5 possibly via natriuretic and diuretic effects in the kidney or inhibitory effects on the renin angiotensin system.17 Alternatively, meat protein increases glomerular filtration rate,18 which may lead to a diureticlike action and lower blood pressure. The beneficial effects of fish protein are most often linked to -3 polyunsaturated fatty acids. Correspondence to: Douglas S. Martin, PhD, University of South Dakota School of Medicine, 414 East Clark Street, Vermillion, SD 57069. E-mail: [email protected] Nutrition 19:385–389, 2003 ©Elsevier Science Inc., 2003. Printed in the United States. All rights reserved.
However, fish protein may contain other active elements that inhibit the renin angiotensin system cascade19 or enhance renal clearance of sodium.20 Ait-Yahia et al. suggest that fish protein acts by altering arachidonic acid metabolism.7 Multiple mechanisms of action also may be in play for soy protein. The role of the isoflavones (genistein and daidzein) in the cardiovascular effects of soy protein has generated considerable interest. In animal models, it appears that isoflavones contribute to the blood pressure– moderating effects of soy.13 In humans, isoflavone supplementation was not associated with attenuation of hypertension in some studies,21 but others have reported an association between isoflavone intake and blood pressure.16 In addition, an angiotensinconverting enzyme inhibitory substance was isolated from soy meal and produced dramatic reduction of pressure in hypertensive animals.22 Alternatively, inhibition of tyrosine kinase pathways may play a role in the antihypertensive effects of genistein.23 Thus, there are many potential mechanisms currently proposed to account for the antihypertensive effect of dietary protein. However, none is particularly well established or proven to act as the hypotensive mechanism in humans. Second, dietary proteins may contain pharmacologically active substances, so it is important to assess not only the mechanisms by which they act but also how dietary proteins interact with other non-pharmacologic and pharmacologic antihypertensive therapies. For example, Burke et al.15 recently described an additive beneficial effect of dietary fiber and dietary soy protein on blood pressure in patients who remained on antihypertensive medications. Third, it is important to understand potential negative effects that dietary protein may have on the cardiovascular and other systems. For example, Teede et al. reported that, although soy protein reduced blood pressure, there was a significant reduction in endothelial function in males.16 It is also essential to understand the effects of consumed protein on renal function. Although dietary animal protein may ameliorate blood pressure, current data suggest that animal protein may have detrimental effects on kidney function,18 particularly in diabetic patients with existing renal dysfunction. In contrast, soy and fish protein may exert renal protective effects in the diabetic kidney.24,25 Fourth, the issue of sex differences needs to be addressed systematically. Some of the proposed mediators, such as the isoflavones, may act via estrogen receptor stimulation. Thus, the background level of sex steroids may alter their effects. Indeed, sex differences have been reported in the effects of dietary soy in humans16 and in animal models of hypertension.12,14 In summary, accumulating evidence in animal models and humans suggests that dietary protein can exert antihypertensive effects. However, there clearly remain many unanswered questions regarding the effects of dietary protein on blood pressure control. The data accumulated to date indicate that this is a promising area that is worthy of expanded basic science and clinical investigation.
Douglas S. Martin, PhD University of South Dakota School of Medicine Vermillion, South Dakota, USA
REFERENCES 1. Frohlich EE, Gifford R, Horan M, et al. Non-pharmacological approaches to the control of high blood pressure. Final report of the subcommittee on nonpharmacological therapy of the 1984 Joint National Committee on Detection, Evaluation and Treatment of High Blood Pressure. Hypertension 1986;8:444
0899-9007/03/$30.00
386
Editorial Opinions
Nutrition Volume 19, Number 4, 2003
2. Sheps SG. The sixth report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of Hypertension. Arch Int Med 1997;157: 2413 3. McCarty MF. Vegan proteins may reduce risk of cancer, obesity and cardiovascular disease by promoting increased glucagon activity. Med Hypotheses 1999; 53:459 4. Hecker KD. Effects of dietary animal and soy protein on cardiovascular disease risk factors. Curr Atheroscler Rep 2001;3:471 5. Obarzanek E, Velletri PA, Cutler JA. Dietary protein and blood pressure. JAMA 1996;275:1598 6. Liu L, Ikeda K, Yamori Y. Inverse relationship between urinary markers of animal protein intake and blood pressure in Chinese: results from the WHO Cardiovascular Diseases and Alimentary Comparison (CARDIAC) study. Int J Epidemiol 2002;31:227 7. Ait-Yahia D, Madani S, Savelli JL, et al. Dietary fish protein lowers blood pressure and alters tissue polyunsaturated fatty acid composition in spontaneously hypertensive rats. Nutrition 2002;19:352 8. Beilin L, Burke V, Puddey IB, Mori TA, Hodgson JM. Recent developments concerning diet and hypertension. Clin Exp Pharmacol Physiol 2001;28:1078 9. Setchell KDR. Phytoestrogens: the biochemistry, physiology, and implications for human health of soy isoflavones. Am J Clin Nutr 1998;68:1333S 10. Setchell KDR, Cassidy A. Dietary isoflavones: biological effects and relevance to human health. J Nutr 1999;129:758S 11. Hayashi U, Nagao K, Yshioka Y. Relationship between food containing “Natto” (fermented soybeans) and the blood pressure of SHR. Jpn Heart J 1976;17:343 12. Martin DS, Breitkopf NP, Eyster KM, Williams JL. Dietary soy exerts an antihypertensive effect in spontaneously hypertensive female rats. Am J Physiol 2001;281:R553 13. Fang Z, Carlson SH, Chen YF, Oparil S, Wyss JM. Estrogen depletion induces NaCl-sensitive hypertension in female spontaneously hypertensive rats. Am J Physiol 2001;281:R1934 14. Nevala R, Vaskonen T, Vehniainen J, Korpela R, Vaatalo H. Soy based diet attenuates the development of hypertension when compared to casein based diet in spontaneously hypertensive rat. Life Sci 2000;66:115 15. Burke V, Hodgson JM, Beilin LJ, et al. Dietary protein and soluble fiber reduce ambulatory blood pressure in treated hypertensives. Hypertension 2001;38:821 16. Teede HJ, Dalais FS, Kotsopoulus D, et al. Dietary soy has both beneficial and potentially adverse cardiovascular effects: a placebo controlled study in men and postmenopausal women. J Clin Endocrinol Metab 2001;86:3053 17. Schaffer SW, Lombardini JB, Azuma J. Interaction between the actions of taurine and angiotensin II. Amino Acids 2000;18:305 18. Mackenzie HS, Taal MW, Luyckx VA, Brenner BM. Adaption to nephron loss. In: Brenner BM, ed. The kidney. Philadelphia, PA: W.B. Saunders Company, 2000:1901 19. Fujita J, Yoshikawa M. LKPNM: a prodrug-type ACE inhibitory peptide derived from fish protein. Immunopharmacology 1999;44:123 20. Wang J, Ikeda K, Kihara M, et al. Sodium preference and excretion in spontaneously hypertensive rats on various diets. Clin Exp Pharmacol Physiol 1985; 12:139 21. Hodgson JM, Puddey IB, Beilin LJ, Mori TA, Burke V. Effects of isoflavonoids on blood pressure in subjects with high normal ambulatory blood pressure: a randomised controlled trial. Am J Hypertens 1999;12:47 22. Wu J, Ding X. Hypotensive and physiological effect of angiotensin converting enzyme inhibitory peptides derived from soy protein on spontaneously hypertensive rats. J Agric Food Chem 2001;49:501 23. Laplante MA, Wu R, Champlain JD. Hypotensive effects of genistein in angiotensin treated hypertensive rats; implication of the ERK-MAPK pathway and the superoxide anion radical. Am J Hypertens 2001;14:25A 24. Maddox D, Alavi FK, Silbernick EM, Zawada ET. Protective effects of a soy diet in preventing obesity-linked renal disease. Kidney Int 2002;61:96 25. Mollsten AV, Dahlquist GG, Stattin EL, Rudberg S. Higher intakes of fish protein are related to a lower risk of microalbuminuria in young Swedish type 1 diabetic patients. Diabetes Care 2001;24:805
PII S0899-9007(02)00952-8
Potential of Essential Fatty Acids as Natural Therapeutic Products for Human Tumors Linoleic (18:2 -6) and ␣-linolenic (18:3 -3) acids, parents of the -6 and -3 polyunsaturated fatty acid (PUFA) families, cannot be synthesized by mammalian cells. Once eaten, they are desaturated and elongated to yield several PUFAs of the same family. The 18:3
-3 and 18:2 -6 essential fatty acids (EFAs) and eventually other non-EFA 18-carbon fatty acids from the -7 and -9 families compete for a common 6-desaturase. Under normal dietary conditions, 18:3 -3 is preferentially desaturated, followed by 18:2 -6, thus avoiding the conversion of 18:1 -9 to the more highly unsaturated -9 metabolites.1–3 In many tumor cells the metabolism of -6 EFA is abnormal because there is a decrease in the activity of the enzyme ␦-6desaturase, which catalyzes the initial desaturation step (i.e., 18:3 -6, or ␥-linolenic acid [GLA]) in the pathway involved in the elaboration of longer-chain -6 PUFAs, whose synthesis becomes progressively diminished.4 – 8 The loss of activity of ␦-6-desaturase also disturbs the levels of long-chain, highly unsaturated fatty acids from the -9 and -7 families in tumor cells.9 Thus, malignant transformation per se causes progressive and intricate fatty acid abnormalities linked to failed obtainment of appropriate eicosanoid substrates8 or the degree of unsaturation of membrane microdomains because unusual long-chained non-EFA -9 and -7 derivatives arise.9,10 Often in tumor tissues the values of long-chain -3 PUFA are not modified.10 This occurrence is not unexpected because most dietary sources of -3 come from seafood oils 18:4, 20:4, and 20:5, which are metabolized by ␦-5desaturase, a pathway that is not significantly altered in tumor cells.5,9,10 Revisions of experimental data have indicated that diets rich in linoleic acid have a consistent tumor-promoting activity in mammary glands and other organs in rodents.11,12 However, most of the evidence in humans is negative; in a large study concerning the intake of 18:2 -6 by nurses, it was shown that the group with the lowest intake of linoleic acid exhibited the highest incidence of breast cancer13 without increasing the risk for colon cancer.14 Despite these findings, the mechanisms involved in these modulating effects remain controversial. In particular, the effects of different families of dietary PUFAs on the prevention and therapy of cancer are far from clear. In this regard it is interesting that Bakshi et al.15 have presented data in this issue of Nutrition indicating that 18:3 -6, GLA, inoculated in the bed of resected gliomas, improved, but not dramatically, survival and other parameters of evolution in patients with advanced stages of the disease. Interestingly, undesirable side effects were not observed when GLA was administered to patients subjected to other well-established approaches such as radiotherapy, chemotherapy plus glucorticoid treatment, or their combination. The rationale proposed by Bakshi et al.15 avoids, or at least mitigates, two closely related metabolic facts in neoplasia: lack of adequate -6 substrate and, as a correlation, a relative EFA deficiency in tumor tissues. The latter condition may be protumorigenic, as proposed 50 y ago by Nyrop16 and Sinclair17,18 and more recently by others.19 –21 Even though the metabolic mechanisms underlying the beneficial effect of GLA instillation is not the main scope of the work by Bakshi et al.,15 Das has investigated the question rather extensively22–24 and his findings are worth some further remarks concerning the issue. First, EFAs and their derivatives, such as GLA, are chief vectors in biomembranes in building and conditioning selective microdomains for protein-made channels, receptors, cell adhesion molecules, and enzymes, thereby influencing vast and complex cellular functions.25,26 EFAs have a role, through a poorly understood mechanism, in the regulation of the rate of normal cell proliferation and differentiation. When cells lack EFAs, increased proliferation and decreased apoptosis result; both protumorigeniCorrespondence to: Aldo R. Eynard, MD, PhD, Instituto de Biologı´a Celular, Facultad de Ciencias Me´ dicas, Universidad Nacional de Co´ rdoba, Casilla de Correos 220, CP 5000 Co´ rdoba, Argentina. E-mail: [email protected]
Dietary Protein and Hypertension: Where Do We Stand? Despite the prevalence of high blood pressure worldwide, this disease generally commands less social awareness than do coronary artery disease and stroke. In addition, because hypertensive patients exhibit few symptoms, they are less likely to seek and obtain treatment. Moreover, compliance with traditional pharmacologic therapy is reduced by unacceptable side effects. Accordingly, there has been a renewed interest in non-pharmacologic antihypertensive therapy. Dietary manipulations are attractive as non-pharmacologic therapy because they can be instituted before diagnosis and may prevent blood pressure elevation. The Dietary Approaches to Stop Hypertension (DASH) trial demonstrated conclusively that moderate dietary manipulation could be successful as nonpharmacologic hypertension treatment. For many years, the focus of dietary intervention has been on intake of electrolytes. Indeed, the Joint National Commission reports on treatment of hypertension only briefly mention dietary protein as a potential approach to modify high blood pressure1,2 citing insufficient research in this area. Since that time, accumulating evidence (albeit sometimes contradictory) has indicated that dietary protein can influence blood pressure. A traditional view, still espoused by some today, had been that consumption of animal protein increases, whereas vegetable protein decreases, blood pressure.3 Nevertheless, there is now substantial data indicating that animal protein intake, in fact, reduces blood pressure.4,5 For example, Liu et al. used an objective measure of animal protein intake (urinary 3-methyl histidine levels) and reported a significant inverse relation between animal protein intake and blood pressure in humans.6 The recent study by Ait-Yahia et al.7 (in this issue of Nutrition) demonstrates a similar effect of dietary fish protein in a hypertensive animal model. Hypertensive patients also experience a significant decrease in blood pressure when fed a diet supplemented with fish.8 Soy protein also may have a beneficial effect on cardiovascular health. Much of the research focus has been on improvement in the plasma lipid profile.9,10 Nevertheless, it was suggested more than 25 y ago that soy foods could also attenuate hypertension.11 My colleagues and I12 and others13,14 have confirmed this effect in animals. Although findings in humans may be somewhat more equivocal, the weight of evidence has suggested that dietary soy protein also lowers blood pressure in patients.15,16 Accordingly, at the present time, animal and human observational studies support the conclusion that dietary protein, from animal, fish, or vegetable sources, can lower blood pressure in the appropriate setting. Although the antihypertensive effect of dietary protein is relatively well established, several issues require further intensive research effort. First, understanding the mechanisms underlying the blood pressure lowering effect of dietary protein is paramount. Currently, there are multiple proposed mechanisms. In the case of animal protein, it has been speculated that certain amino acids such as taurine may exert a blood pressure lowering effect,4,5 possibly via natriuretic and diuretic effects in the kidney or inhibitory effects on the renin angiotensin system.17 Alternatively, meat protein increases glomerular filtration rate,18 which may lead to a diureticlike action and lower blood pressure. The beneficial effects of fish protein are most often linked to -3 polyunsaturated fatty acids. Correspondence to: Douglas S. Martin, PhD, University of South Dakota School of Medicine, 414 East Clark Street, Vermillion, SD 57069. E-mail: [email protected] Nutrition 19:385–389, 2003 ©Elsevier Science Inc., 2003. Printed in the United States. All rights reserved.
However, fish protein may contain other active elements that inhibit the renin angiotensin system cascade19 or enhance renal clearance of sodium.20 Ait-Yahia et al. suggest that fish protein acts by altering arachidonic acid metabolism.7 Multiple mechanisms of action also may be in play for soy protein. The role of the isoflavones (genistein and daidzein) in the cardiovascular effects of soy protein has generated considerable interest. In animal models, it appears that isoflavones contribute to the blood pressure– moderating effects of soy.13 In humans, isoflavone supplementation was not associated with attenuation of hypertension in some studies,21 but others have reported an association between isoflavone intake and blood pressure.16 In addition, an angiotensinconverting enzyme inhibitory substance was isolated from soy meal and produced dramatic reduction of pressure in hypertensive animals.22 Alternatively, inhibition of tyrosine kinase pathways may play a role in the antihypertensive effects of genistein.23 Thus, there are many potential mechanisms currently proposed to account for the antihypertensive effect of dietary protein. However, none is particularly well established or proven to act as the hypotensive mechanism in humans. Second, dietary proteins may contain pharmacologically active substances, so it is important to assess not only the mechanisms by which they act but also how dietary proteins interact with other non-pharmacologic and pharmacologic antihypertensive therapies. For example, Burke et al.15 recently described an additive beneficial effect of dietary fiber and dietary soy protein on blood pressure in patients who remained on antihypertensive medications. Third, it is important to understand potential negative effects that dietary protein may have on the cardiovascular and other systems. For example, Teede et al. reported that, although soy protein reduced blood pressure, there was a significant reduction in endothelial function in males.16 It is also essential to understand the effects of consumed protein on renal function. Although dietary animal protein may ameliorate blood pressure, current data suggest that animal protein may have detrimental effects on kidney function,18 particularly in diabetic patients with existing renal dysfunction. In contrast, soy and fish protein may exert renal protective effects in the diabetic kidney.24,25 Fourth, the issue of sex differences needs to be addressed systematically. Some of the proposed mediators, such as the isoflavones, may act via estrogen receptor stimulation. Thus, the background level of sex steroids may alter their effects. Indeed, sex differences have been reported in the effects of dietary soy in humans16 and in animal models of hypertension.12,14 In summary, accumulating evidence in animal models and humans suggests that dietary protein can exert antihypertensive effects. However, there clearly remain many unanswered questions regarding the effects of dietary protein on blood pressure control. The data accumulated to date indicate that this is a promising area that is worthy of expanded basic science and clinical investigation.
Douglas S. Martin, PhD University of South Dakota School of Medicine Vermillion, South Dakota, USA
REFERENCES 1. Frohlich EE, Gifford R, Horan M, et al. Non-pharmacological approaches to the control of high blood pressure. Final report of the subcommittee on nonpharmacological therapy of the 1984 Joint National Committee on Detection, Evaluation and Treatment of High Blood Pressure. Hypertension 1986;8:444
0899-9007/03/$30.00
386
Editorial Opinions
Nutrition Volume 19, Number 4, 2003
2. Sheps SG. The sixth report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of Hypertension. Arch Int Med 1997;157: 2413 3. McCarty MF. Vegan proteins may reduce risk of cancer, obesity and cardiovascular disease by promoting increased glucagon activity. Med Hypotheses 1999; 53:459 4. Hecker KD. Effects of dietary animal and soy protein on cardiovascular disease risk factors. Curr Atheroscler Rep 2001;3:471 5. Obarzanek E, Velletri PA, Cutler JA. Dietary protein and blood pressure. JAMA 1996;275:1598 6. Liu L, Ikeda K, Yamori Y. Inverse relationship between urinary markers of animal protein intake and blood pressure in Chinese: results from the WHO Cardiovascular Diseases and Alimentary Comparison (CARDIAC) study. Int J Epidemiol 2002;31:227 7. Ait-Yahia D, Madani S, Savelli JL, et al. Dietary fish protein lowers blood pressure and alters tissue polyunsaturated fatty acid composition in spontaneously hypertensive rats. Nutrition 2002;19:352 8. Beilin L, Burke V, Puddey IB, Mori TA, Hodgson JM. Recent developments concerning diet and hypertension. Clin Exp Pharmacol Physiol 2001;28:1078 9. Setchell KDR. Phytoestrogens: the biochemistry, physiology, and implications for human health of soy isoflavones. Am J Clin Nutr 1998;68:1333S 10. Setchell KDR, Cassidy A. Dietary isoflavones: biological effects and relevance to human health. J Nutr 1999;129:758S 11. Hayashi U, Nagao K, Yshioka Y. Relationship between food containing “Natto” (fermented soybeans) and the blood pressure of SHR. Jpn Heart J 1976;17:343 12. Martin DS, Breitkopf NP, Eyster KM, Williams JL. Dietary soy exerts an antihypertensive effect in spontaneously hypertensive female rats. Am J Physiol 2001;281:R553 13. Fang Z, Carlson SH, Chen YF, Oparil S, Wyss JM. Estrogen depletion induces NaCl-sensitive hypertension in female spontaneously hypertensive rats. Am J Physiol 2001;281:R1934 14. Nevala R, Vaskonen T, Vehniainen J, Korpela R, Vaatalo H. Soy based diet attenuates the development of hypertension when compared to casein based diet in spontaneously hypertensive rat. Life Sci 2000;66:115 15. Burke V, Hodgson JM, Beilin LJ, et al. Dietary protein and soluble fiber reduce ambulatory blood pressure in treated hypertensives. Hypertension 2001;38:821 16. Teede HJ, Dalais FS, Kotsopoulus D, et al. Dietary soy has both beneficial and potentially adverse cardiovascular effects: a placebo controlled study in men and postmenopausal women. J Clin Endocrinol Metab 2001;86:3053 17. Schaffer SW, Lombardini JB, Azuma J. Interaction between the actions of taurine and angiotensin II. Amino Acids 2000;18:305 18. Mackenzie HS, Taal MW, Luyckx VA, Brenner BM. Adaption to nephron loss. In: Brenner BM, ed. The kidney. Philadelphia, PA: W.B. Saunders Company, 2000:1901 19. Fujita J, Yoshikawa M. LKPNM: a prodrug-type ACE inhibitory peptide derived from fish protein. Immunopharmacology 1999;44:123 20. Wang J, Ikeda K, Kihara M, et al. Sodium preference and excretion in spontaneously hypertensive rats on various diets. Clin Exp Pharmacol Physiol 1985; 12:139 21. Hodgson JM, Puddey IB, Beilin LJ, Mori TA, Burke V. Effects of isoflavonoids on blood pressure in subjects with high normal ambulatory blood pressure: a randomised controlled trial. Am J Hypertens 1999;12:47 22. Wu J, Ding X. Hypotensive and physiological effect of angiotensin converting enzyme inhibitory peptides derived from soy protein on spontaneously hypertensive rats. J Agric Food Chem 2001;49:501 23. Laplante MA, Wu R, Champlain JD. Hypotensive effects of genistein in angiotensin treated hypertensive rats; implication of the ERK-MAPK pathway and the superoxide anion radical. Am J Hypertens 2001;14:25A 24. Maddox D, Alavi FK, Silbernick EM, Zawada ET. Protective effects of a soy diet in preventing obesity-linked renal disease. Kidney Int 2002;61:96 25. Mollsten AV, Dahlquist GG, Stattin EL, Rudberg S. Higher intakes of fish protein are related to a lower risk of microalbuminuria in young Swedish type 1 diabetic patients. Diabetes Care 2001;24:805
PII S0899-9007(02)00952-8
Potential of Essential Fatty Acids as Natural Therapeutic Products for Human Tumors Linoleic (18:2 -6) and ␣-linolenic (18:3 -3) acids, parents of the -6 and -3 polyunsaturated fatty acid (PUFA) families, cannot be synthesized by mammalian cells. Once eaten, they are desaturated and elongated to yield several PUFAs of the same family. The 18:3
-3 and 18:2 -6 essential fatty acids (EFAs) and eventually other non-EFA 18-carbon fatty acids from the -7 and -9 families compete for a common 6-desaturase. Under normal dietary conditions, 18:3 -3 is preferentially desaturated, followed by 18:2 -6, thus avoiding the conversion of 18:1 -9 to the more highly unsaturated -9 metabolites.1–3 In many tumor cells the metabolism of -6 EFA is abnormal because there is a decrease in the activity of the enzyme ␦-6desaturase, which catalyzes the initial desaturation step (i.e., 18:3 -6, or ␥-linolenic acid [GLA]) in the pathway involved in the elaboration of longer-chain -6 PUFAs, whose synthesis becomes progressively diminished.4 – 8 The loss of activity of ␦-6-desaturase also disturbs the levels of long-chain, highly unsaturated fatty acids from the -9 and -7 families in tumor cells.9 Thus, malignant transformation per se causes progressive and intricate fatty acid abnormalities linked to failed obtainment of appropriate eicosanoid substrates8 or the degree of unsaturation of membrane microdomains because unusual long-chained non-EFA -9 and -7 derivatives arise.9,10 Often in tumor tissues the values of long-chain -3 PUFA are not modified.10 This occurrence is not unexpected because most dietary sources of -3 come from seafood oils 18:4, 20:4, and 20:5, which are metabolized by ␦-5desaturase, a pathway that is not significantly altered in tumor cells.5,9,10 Revisions of experimental data have indicated that diets rich in linoleic acid have a consistent tumor-promoting activity in mammary glands and other organs in rodents.11,12 However, most of the evidence in humans is negative; in a large study concerning the intake of 18:2 -6 by nurses, it was shown that the group with the lowest intake of linoleic acid exhibited the highest incidence of breast cancer13 without increasing the risk for colon cancer.14 Despite these findings, the mechanisms involved in these modulating effects remain controversial. In particular, the effects of different families of dietary PUFAs on the prevention and therapy of cancer are far from clear. In this regard it is interesting that Bakshi et al.15 have presented data in this issue of Nutrition indicating that 18:3 -6, GLA, inoculated in the bed of resected gliomas, improved, but not dramatically, survival and other parameters of evolution in patients with advanced stages of the disease. Interestingly, undesirable side effects were not observed when GLA was administered to patients subjected to other well-established approaches such as radiotherapy, chemotherapy plus glucorticoid treatment, or their combination. The rationale proposed by Bakshi et al.15 avoids, or at least mitigates, two closely related metabolic facts in neoplasia: lack of adequate -6 substrate and, as a correlation, a relative EFA deficiency in tumor tissues. The latter condition may be protumorigenic, as proposed 50 y ago by Nyrop16 and Sinclair17,18 and more recently by others.19 –21 Even though the metabolic mechanisms underlying the beneficial effect of GLA instillation is not the main scope of the work by Bakshi et al.,15 Das has investigated the question rather extensively22–24 and his findings are worth some further remarks concerning the issue. First, EFAs and their derivatives, such as GLA, are chief vectors in biomembranes in building and conditioning selective microdomains for protein-made channels, receptors, cell adhesion molecules, and enzymes, thereby influencing vast and complex cellular functions.25,26 EFAs have a role, through a poorly understood mechanism, in the regulation of the rate of normal cell proliferation and differentiation. When cells lack EFAs, increased proliferation and decreased apoptosis result; both protumorigeniCorrespondence to: Aldo R. Eynard, MD, PhD, Instituto de Biologı´a Celular, Facultad de Ciencias Me´ dicas, Universidad Nacional de Co´ rdoba, Casilla de Correos 220, CP 5000 Co´ rdoba, Argentina. E-mail: [email protected]