Selective effects of N-acetylcysteine stereoisomers on hepatic glutathione and plasma sulfate in mice.

Administration of 1200 mg/kg N-acetyl-L-acetyl-L-cysteine to mice apparently increased the rate of glutathione synthesis resulting in prolonged elevation of the hepatic glutathione pool. At 3 hr, peak glutathione concentrations nearly doubled. The fraction of glutathione in the oxidized state remained at normally low values over this period. The L isomer also significantly increased plasma and urinary concentrations of inorganic sulfate. Plasma concentrations nearly doubled at their peak and urinary excretion over 24 hr rose some threefold above control. Consistent with the known stereoselectivity of many biological processes, the unnatural D isomer of N-acetylcysteine failed to increase hepatic glutathione. Liver concentrations remained similar to control suggesting that the D isomer was unable to increase the rate of glutathione synthesis. The D isomer further differed from its L enantiomer in failing to increase the plasma concentration and the urinary excretion of inorganic sulfate. Congruent with these observations, much more N-acetyl-D-cysteine (47% of dose) was recovered unchanged in 24 hr urine than N-acetyl-L-cysteine (6.1% of dose). These findings are of toxicologic interest because they identify the N-acetylcysteine stereoisomers as a pair of agents that may be useful in separating biologic effects of sulfhydryls that are related primarily to their physical properties (i.e. reduction, radical scavenging) from those that accrue from their ability to increase glutathione and sulfate availability in vivo.