Methionine supplementation.
Whether excess of dietary methionine intake in humans is atherogenic remains to be determined; however, considerable evidence from animal experiments suggests that these findings are not limited to the ApoE-deficient mouse model. A similar experimental dissociation of hyperhomocysteinemia and atherosclerosis has been observed in pigs and primates fed atherogenic diets (21, 59). Ambrosi et al. (21) showed that feeding pigs a methionine-rich diet for 4 months induced hyperhomocysteinemia and atherosclerosis. Folate supplementation of the methionine-rich diet successfully normalized plasma homocysteine levels but did not reduce methionine-induced vascular lesions.
Similarly, when Lentz et al. fed cynomolgus monkeys a high-fat and -cholesterol diet for 13–26 months, it induced not only hypercholesterolemia and atherosclerosis, but also hyperhomocysteinemia and B vitamin deficiency. When the same diet was supplemented with folic acid, vitamin B12, and vitamin B6, blood vitamin and homocysteine levels were normalized, but no attenuation of atherosclerosis or vascular dysfunction occurred in supplemented monkeys.
It is difficult to reconcile these data with the observation that rare congenital defects in homocysteine metabolism are associated with premature thrombotic and arteriosclerotic disease, whether the defects are in genes of the transsulfuration pathway (which are associated with elevated methionine) or of the methylation pathway (which are associated with low methionine).
This observation has often been cited as key evidence supporting the view that vascular disease in hyperhomocysteinemia and particularly atherosclerosis is due to homocysteine per se rather than an effect of its metabolic determinants. Nevertheless, attempts to mimic these human conditions in knockout mice that are defective in transsulfuration or in the remethylation remethylation of homocysteine have so far not induced either arteriosclerosis or atherosclerosis in these models despite achieving hyperhomocysteinemia. This finding leaves unanswered which aspects of vascular pathology might be causally linked to homocysteine or whether additional factors might be necessary for the putative vasotoxic properties of homocysteine to become apparent.
Although the role of homocysteine in atherosclerosis remains to be determined, the atherogenic potency of excess methionine intake is a well documented, if often overlooked, phenomenon. Abundant data on dietary amino acid imbalances describe "methionine toxicity" that leads to growth retardation and histopathologic changes in liver, kidney, and spleen, at methionine intake as low as 2% of diet. Numerous studies show high methionine intake to produce atherosclerotic changes in mice rats, rabbits, and pigs, even if the results have often been attributed to a coincident rise in plasma homocysteine.
Further evidence of methionine’s vascular toxicity can be derived from studies that examine the vascular effect of dietary protein content and composition. For example, high methionine casein based diets promote vascular pathology in ApoE-deficient mice to a greater extent than low methionine isoflavone-free soy-protein-based diets even within the range of normal dietary methionine intake and similar total protein content. Together, these observations demonstrate that methionine toxicity is not limited to the ApoE-deficient mouse model. Additional studies are needed to determine the mechanism that underlies this atherogenic property of excess dietary methionine and whether this mechanism could at least in part explain the epidemiological association between elevated homocysteine levels and cardiovascular disease. |
