Effect of N-acetylcysteine long term oral administration on plasma and urinary homocysteine and cysteine levels

Background: A decrease of plasma homocysteine (Hcy) may represent a therapeutic promise for reducing the impact of atherosclerosis. N-acetyl-cysteine (NAC) at high dosage seems able to interfere with endogenous thiols [cysteine (Cys) and Hcy] by forming mixed disulphides undergoing a more efficient renal clearance. Aim : to assess the effect of NAC oral chronic administration (different doses) on plasma and urine levels of different forms of plasma Cys and Hcy. Methods: In 40 healthy (44±15 years, 22 F) we assessed fasting total and free (= not protein bound) forms of plasma and urinary levels of Hcy and Cys. After informed consent subjects were randomly assigned to group A (n= 13, no therapy), group B (n= 14, NAC 600 mg once daily per os) and group C (n= 14, NAC once daily 1800 mg per os) for a month. Results: Group C showed a significant reduction of total Hcy (10.68  2.8 vs. 13.64  3.56 mmol/L, p= .001) a not significant reduction of free Hcy (3.48  0.72 vs. 3.55  0.74 mol/L, p=.702) a significant reduction of total Cys (320  93 vs. 377  122 mol/L, p=.013) a not significant reduction of free Cys (147  26.5 vs. 162  40.6 mol/L, p= .294), a significant increase of free/bound Hcy and Cys ratio (33.2  3.21 vs. 26.5  3.7 %, p= .000 and 48  7.6 vs. 42  6.0 %, p=.045, respectively).Group B showed a significant reduction of total plasma Hcy (11.6 3.7 vs. 12.88  3.9 mol/L, p=0.031) but not significant modification of other thiols forms levels.After NAC therapy Group C showed also significant higher daily Hcy and Cys urinary levels (11.73.5 vs. 9.13.1 mmol/ mg urinary creatinine , p<0.01, 24773 vs. 22074 mmol/ mg urinary creatinine, p=0.011).Also group B showed higher, but not significant, Hcy and Cys urinary levels (11.24.2 vs 10.513.3 mol/ mg urinary creatinine, p=0.056 and 23949 vs 22955 mol/ mg urinary creatinine, p=0.055). No significant variations in plasma and urinary thiols were noticed in group A.Conclusions: A chronic (one month) oral NAC administration induces a decrease of the main circulating plasma thiols (Cys and Hcy) by increasing their renal excretion. This effect seems dose-dependent, being significant only at higher NAC dosage; the modification of plasma thiols forms (reduction of total and free forms but increase of free/total ratio) support the hypothesis of displacement by NAC of thiols from their plasma protein binding sites to form mixed disulphides, which in turns may undergo a higher renal clearance, resulting in an increase of urinary excretion.