Over the past decade, creatine has become a popular dietary supplement among professional and recreational athletes because of its reported beneficial effects on exercise performance.1 With worldwide annual consumption estimated to be approximately 2.5 ×106 kg, it can currently be classed as one of the world's best-selling dietary supplements.1 An increase in creatine intake will suppress endogenous production of creatine.2,3 Under normal conditions, creatine synthesis in the liver accounts for nearly 75% of daily homocysteine formation4,5 (Figure 1). An elevated plasma homocysteine concentration is considered an important independent risk factor in the development of cardiovascular disease6; therefore, it is important to establish whether dietary creatine supplementation influences plasma homocysteine concentration. One might predict that an increase in exogenous creatine supply would decrease plasma homocysteine concentration as a consequence of diminished endogenous creatine production (Figure 1), but there are currently no published data available to support this contention. Therefore, the first aim of our study (conducted in the spring of 1998) was to investigate whether prolonged creatine supplementation influenced plasma homocysteine concentration in healthy volunteers.
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Schematic representation of interaction between creatine and homocysteine metabolism. An increase in circulating creatine inhibits the activity of the enzyme required for reaction 1 (ie, arginine:glycine amidinotransferase). Consequently, S-adenosylmethionine (SAM) levels rise, which has been proposed to enhance reactions 3 and 4 and to suppress reaction 5. Under normal conditions (ie, normal creatine intake) methionine will interact with guanidinoacetate to form homocysteine (reaction 2, unbroken arrow). The broken arrow (reaction 3) indicates our speculation that this reaction will take place under conditions of high creatine intake, thereby maintaining homocysteine formation. SAH indicates S-adenosylhomocysteine; THF, tetrahydrofolate.
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