Oral Creatine Supplements Lower Plasma Homocysteine Concentrations in Humans

Clinical Laboratory Science, Spring 2004 by Korzun, William J

OBJECTIVE: To determine if oral creatine supplements will lower the concentration of total plasma homocysteine (tHcy).

SETTING/PARTICIPANTS: Apparently healthy volunteers, at least 19 years old, were recruited from the University of South Alabama and surrounding community.

DESIGN/INTERVENTION/MAIN OUTCOME: Participants took multi-vitamins daily for four weeks, then were randomly divided into two groups. The control group (C) continued, to take multi-vitamins daily for an additional four weeks. The experimental group (EX) took multivitamins plus an amount of creatine each day equal to twice their daily creatinine excretion, for the additional four weeks. Total plasma homocysteine concentrations were measured in all participants at the beginning and at the end of the second four week interval.

RESULTS: There were no statistically significant differences between the two groups in age, initial tHcy, serum folate, erythrocyte folate, serum vitamin B12, or creatinine excretion. After four weeks of creatine supplements, tHcy in EX changed by an average of -0.9 µmol/L (range: -1.8 to 0.0), compared to an average change of 0.2 µmol/L in C (range: -0.6 to 0.9) during the same four weeks. The difference in the changes in tHcy between the two groups was statistically significant (p

CONCLUSION: Creatine supplements may be an effective adjunct to vitamin supplements for lowering tHcy.

ABBREVIATIONS: C = group of participants taking only multivitamins; EX = group of participants taking multivitamins plus creatine; Hcy = homocysteine; SAH = S-adenosylhomocysteine; SAM = S-adenosylmethionine; tHcy = concentration of total plasma homocysteine.

INDEX TERMS: creatine; homocysteine; human.

Clin Lab Sci 2004;17(2):102

Hyperhomocysteinemia is a risk factor for the development of cardiovascular disease in humans. 1-4 Homocysteine (Hey) is a by-product of metabolic pathways in which methyl groups are transferred from S-adenosylmethionine (SAM) to 'acceptor' substrates. These include the biosynthetic pathways for creatine, epinephrine, phosphatidylcholine, and the methylation of DNA and RNA. In most tissues, Hey is eliminated by remethylation to methionine, which requires adequate intake of vitamin B12 and folic acid. The liver also has the capacity to eliminate Hey by transsulfuration to cysteine, dependent on an adequate intake of vitamin B6, and to remethylate Hcy to methionine utilizing betaine as the methyl donor.5 Hcy that cannot be metabolized by these tissue pathways is exported to the blood and contributes to the total plasma homocysteine concentration (tHcy).2 Dietary supplements containing the three vitamins required for the elimination of Hey have been shown to reduce tHcy in a variety of settings.6-8 However, the effect of obviating the homocysteine-generating pathways on tHcy has not been extensively studied.

Each day, the average individual loses, depending on muscle mass, 10 to 15 millimoles of creatine due to spontaneous degradation to creatinine. Biosynthesis of creatine, to replace that loss, involves two enzyme-catalyzed reactions. In the first reaction, the amidino group of arginine is transferred to glycine, forming guanidinoacetate and ornithine. In the second reaction, a methyl group is transferred from SAM to guanidinoacetate to form creatine and S-adenosylbomocysteine (SAH). SAH is subsequently hydrolyzed to adenosine and Hcy, thus generating one molecule of Hcy for each molecule of creatine synthesized. It has been estimated that creatine biosynthesis could potentially account for up to 75% of daily Hcy production.5 High levels of exogenously provided creatine can repress the synthesis of the enzyme that catalyzes the first step in creatine biosynthesis in chick embryo livers and in rat kidneys.9,10 Furthermore, rats fed a creatine-enriched diet had decreased tHcy compared to controls.11 Oral creatine supplements are commonly used by athletes to enhance performance.12,13 Studies involving creatine supplements in healthy individuals have failed to produce reports of adverse effects.12-17 Therefore, this study was undertaken to determine if oral creatine supplements could lower tHcy in healthy volunteers. While this study was in progress, it was reported that creatine supplementation produced a small but statistically insignificant decrease in tHcy in healthy women, with or without a concurrent program of resistance training.18

MATERIALS AND METHODS

This study was approved by the Institutional Review Board of the University of South Alabama. Volunteers claiming to be in good health were recruited from the University and surrounding community. A total of 19 subjects gave written, informed consent after the study design and procedures were verbally explained to them.

Pure creatine monohydrate (C^sub 4^H^sub 9^N^sub 3^O^sub 2^*H^sub 2^O, molecular weight = 149 g/mole) was purchased from Experimental and Applied Sciences, Golden CO. One-a-day multivitamins (Centrum) were purchased from a local retailer. Each vitamin tablet reportedly contained 100% of the current recommended daily allowances of folic acid (400 µg), vitamin B12 (6 µg), and vitamin B6 (2 mg).