Taurine: red bull or red herring?

Taurine, a sulfur-containing amino acid (Figure), has been termed a functional nutrient that could be used to protect against, among others, diabetes mellitus and atherosclerosis.1 Indeed, an increasing body of literature supports the use of taurine supplements. Because taurine has very diverse functions, notably, intracellular osmoregulation and bile acid formation, and is abundantly present in several organs, multiple pathways could be involved. Some of these are discussed in this editorial. Of the 20 canonical amino acids, 18 are composed of carbon, hydrogen, nitrogen, and oxygen only. The remaining 2, methionine and cysteine, also contain 1 atom of sulfur. Because sulfur is not as electronegative as oxygen, the sulfurcontaining amino acids play a key role in protein structure and synthesis.2 Methionine and cysteine also play important roles in cell metabolism. For instance, methionine serves as a substrate for S-adenosylmethionine, which is vital for methylation of nucleic acids, proteins, lipids, etc. In proteins, cysteine easily forms double bonds with other cysteine residues, thus determining tertiary structure and binding sites. Moreover, cysteine is substrate for glutathione, an important intracellular antioxidant, and H2S, a gas that can induce endothelial-dependent relaxation.3 Cysteine is considered a nonessential amino acid because it is synthesized from the essential amino acid methionine. However, because homocysteine lies in the pathway between methionine and cysteine, excess methionine induces hyperhomocysteinemia, a risk factor for atherosclerosis. Dietary hypercholesterolemia leads to coronary atherosclerosis in rabbits,4 and maternal hypercholesterolemia can even lead to fatty streaks in the aorta of the human fetus.5 Dietary methionine induced hyperhomocysteinemia in rabbits, but this in itself does not induce atherosclerosis in the coronary artery.6 However, coronary atherosclerosis induced by dietary hypercholesterolemia was exacerbated by dietary methionine in rabbits,6 and this combination also induced cardiac fibrosis.7 In this issue of Hypertension, Zulli et al8 present data showing in this model that dietary taurine, a downstream metabolite of methionine and cysteine, can ameliorate coronary atherosclerosis and also prevent hyperhomocysteinemia and ameliorated hypermethionemia. This observation raises a number of questions: (1) is there negative feedback by taurine on its own metabolic pathway; (2) if so, is the protective effect of taurine dependent on a reduction in homocysteine; (3) does taurine have antiatherosclerotic effects that are not related to its metabolic pathway; and (4) is dietary taurine supplementation always safe. In our opinion, answers to these questions are required before taurine supplementation can be tested in a controlled clinical trial. Direct effects of taurine on its own metabolic pathway have not been described. However, taurine inhibits methionine uptake in intestinal Caco-2 cells.9 This inhibitory effect occurs because taurine and methionine share the B transporter. This may explain why the high plasma methionine levels induced by dietary methionine in the rabbits studied by Zulli et al8 were initially reduced by dietary taurine. Because this inhibitory effect occurs on the apical side of the intestine, this could occur without an increase in plasma taurine. Indeed, dietary taurine had practically no effect on plasma taurine levels. Furthermore, after 4 weeks of dietary cholesterol plus methionine (and taurine), plasma levels of methionine and homocysteine had normalized, suggesting that, by the end of the experimental period, methionine uptake was completely inhibited by taurine. High methionine intake can lead to hyperhomocysteinemiainduced toxicity. Tenfold increases in homocysteine levels lead to myocardial mitochondrial injury10 and hepatitis.11 Both effects can be reversed by taurine but, surprisingly, without any effect on these very high plasma homocysteine levels.10,11 These studies suggest that, even if high methionine intake leads to severe hyperhomocysteinemia, protective effects of taurine can occur, presumably via intracellular events that are not dependent on a reduction of homocysteine levels. Apparently protective effects of taurine need not be related to direct effects on its own metabolic pathway. Hence, the normalization of high methionine-induced hyperhomocysteinemia by dietary taurine observed in rabbits by Zulli et al8 may be a coincident phenomenon not related to the antiatherosclerotic effect of taurine. Several intracellular effects of taurine are potentially protective. Taurine reduces oxidative stress induced by binding hypochlorite. A novel hypothesis is that taurine conjugates to mitochondrial transfer RNA and, thus, prevents formation of mitochondrial superoxide.12 Taurine can inhibit homocysteineinduced stress of the endoplasmic reticulum of vascular smooth muscle cells and so restore expression and secretion of extracellular superoxide dismutase.13 How this works is unknown, but one possibility is intracellular conjugation of taurine to other molecules. For instance, taurine-conjugating ursodeoxycholic acid increases the water solubility of this bile acid. The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association. From the Department of Nephrology and Hypertension, University Medical Center Utrecht, Utrecht, The Netherlands. Correspondence to Jaap A. Joles, Department of Nephrology and Hypertension F03.223, University Medical Center Utrecht, PO Box 85500, 3508 GA Utrecht, The Netherlands. E-mail [email protected] (Hypertension. 2009;53:909-911.) © 2009 American Heart Association, Inc.