N-acetyl-cysteine reduces homocysteine plasma levels after single intravenous administration by increasing thiols urinary excretion

A decrease of plasma homocysteine (Hcy) may represent a therapeutic promise for reducing the impact of atherosclerosis. N-Acetyl-cysteine (NAC) is a thiol-containing compound interfering with endogenous thiols, cysteine (Cys) and Hey, by forming with them mixed disulphides with a possibly more efficient renal clearance. The aim of this work was to assess the effect of NAC intravenous infusion on plasma levels of different forms of Hey and particularly to verify the effect on Hey renal excretion. We collected basal blood samples at 0.5, 1, 2, 5, 8 and 24 h after the beginning of NAC infusion (50 mg kg-l body wt.) and also 24-h urine samples of the day of NAC infusion and of the day before and of the day after the infusion in ten healthy subjects (mean age 73 +/- 15). Urinary and plasma thiols (Hcy, Cys and NAG) were assayed by HPLC. Both total plasma Hey (approx. 69% vs basal values) and Cys (approx. 40% vs basal values) fell progressively, reaching a minimum 5 h after infusion start; total free (i.e. not bound to proteins) Hey (2.2 +/- 1.8 down from 4.4 +/- 4.2 nmol ml(-1)) and Cys (70.4 +/- 39.8 down from 113.3 +/- 61.2 nmol ml(-1)) decreased as well. Reduced (thiolic-free form) Hey and Cys decreased during infusion, though not as pronounced as for the other forms. Percentagewise, out of the total plasma levels, Hey and Cys total free form and reduced form tended to increase over infusion as well as their difference (i.e. the plasma mixed disulphide moiety), thus supporting the idea that excess NAC displaces thiols from their plasma binding sites forming mixed disulphides. Urinary total Cys and Hey excretion significantly increased at the end of the day of NAC infusion (tenfold for Cys and fivefold for Hey) and reduced appreciably on the following day. Also urinary excretion of the free form of Cys and Hey increased at the end of the day of NAC infusion, although in a lower amount with respect of total amounts, meaning a reduction of percentage Cys and Hey excreted as the free form; for none of the patients had proteinuria, the ´free´ form of urine thiols has to be identified in the ´reduced´ form, the difference between the total and free form reflecting the ´mixed disulphide´ moiety. NAC intravenous administration induces an efficient and rapid reduction of plasma thiols, particularly of Hey; our data support the hypothesis that NAC displaces thiols from their binding protein sites and forms, in excess of plasma NAG, mixed disulphides (NAC-Hcy) with an high renal clearance. This effect may represent the start of an alternative approach in the treatment of hyperhomocysteinaemic conditions.