N-Acetylcysteine in handgrip exercise: plasma thiols and adverse reactions

Journal Title (Medline/Pubmed accepted abbreviation): Int J Sport Nutr Exerc Metab
Year: 2011
Volume: 21
Number: 2
Page numbers: 146-154
doi (if applicable): N/A

Summary of Background and Research Design

Background: N-Acetylcysteine (NAC), a thiol donor with nonspecific antioxidant properties, has been shown in previous studies to delay skeletal muscle fatigue, probably by increasing circulating and myocyte levels of cysteine (CySH) and glutathione (GSH). However, use of NAC to combat fatigue can be limited by adverse reactions, which are typically gastrointestinal (GI), occur within the first hour of exposure, and seem to be dose dependent. In the literature, doses of NAC used to test effects on performance span a 15-fold range, and the effect of NAC dose-dependence on GSH regulation or adverse reactions during exercise has not been evaluated.

Hypothesis/purpose of study: The authors hypothesized that (1) effects of NAC are dose-dependent, (2) all doses of NAC tested (9 to 140 mg/kg) would increase plasma GSH, and (3) adverse reactions would be most prevalent at high doses.

Subjects: Seventeen healthy individuals participated in the study (mean age, 30 ± 2 yr; body weight, 86 ± 5 kg).

Experimental design: Double-blind, placebo-controlled, crossover

Treatments and protocol: Healthy individuals ingested NAC capsules in Arm 1 (0, ~9, or ~18 mg/kg) or solution in Arm 2 (0, 35, 70, or 140 mg/kg) the day before a handgrip exercise test, which consisted of 3 maximal voluntary contractions of ~5 seconds’ duration, separated by 1 minutes’ rest, followed by a sequence of repetitive isometric contractions (3 sec on, 3 sec off). Venous blood samples were collected and analyzed for GSH, oxidized GSH (GSSG), CySH, cystine (CySS), and CySH-GSH disulfide (CySSG). Within 5 to 10 minutes of finishing an exercise bout, individuals answered a questionnaire to identify and describe any adverse reactions experienced.

Summary of research findings
  • NAC capsules (low-dose: ~9, or ~18 mg/kg) did not affect plasma CySH or GSH, or cause adverse reactions.
  • Exposure to NAC solution (high-dose: 35, 70, or 140 mg/kg) resulted in adverse reactions that were mainly mild and GI-related.
    • Intensity of GI adverse reactions to 140 mg/kg NAC was significantly higher than placebo (0.67 ± 0.16 vs 0.07 ± 0.04, respectively; P < .05).
  • Plasma CySH concentrations increased with NAC dose as the NAC dose ranged from 9.3 ± 0.7 µM (placebo) to 65.3 ± 6.7 µM (140 mg/kg); however, there was no difference (P > .05) in plasma CySH for 70 mg/kg vs 140 mg/kg.
  • Similar increases were observed for the plasma CySH:total CySH ratio, which was directly related to all 3 indicators of handgrip exercise performance used in the study.
  • Plasma GSH was elevated and GSSG diminished (P < .05) with NAC 140 mg/kg vs placebo.

Interpretation of findings/Key practice applications

In this study, the effects of NAC on adverse GI reactions and on the concentration and redox state of plasma CySH and GSH were dose dependent. The most frequent GI-related side effects reported were nausea, upset stomach, and intestinal gas; however, none of the participants experienced vomiting, which is the main limitation to oral NAC administration. Therefore, the results suggest that the oral NAC formulation used was well-tolerated by healthy individuals. NAC promoted GSH reduction in the plasma without affecting total GSH levels. The stability of total GSH suggests that NAC solution may have altered redox status by directly reacting with GSSG. At 70 mg/kg, adverse reactions of NAC remain insignificant, whereas plasma levels of CySH and the plasma CySH:total CySH ratio are maximized, suggesting that this may be the optimal dose of NAC for ergogenic testing.
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