A therapeutic trial with N-acetylcysteine in subjects with hereditary glutathione synthetase deficiency (5-oxoprolinuria).

In a therapeutic trial, the effect of short-term low-dosage N-acetylcysteine supplementation on glutathione metabolism was investigated in two patients with hereditary glutathione deficiency (5-oxoprolinuria). Clinical and neurophysiological examinations of the patients indicated progressive neurological damage. The pretreatment concentrations of total and free glutathione in leukocytes were 15-20% of normal, whereas the corresponding gamma-glutamylcysteine levels were increased. In plasma, the glutathione concentrations were similarly decreased, but no gamma-glutamylcysteine was detected. Total glutathione in erythrocytes was markedly decreased. Low urinary excretion of cysteinylglycine, cyst(e)ine, taurine, N-acetylcysteine, mercaptolactate and mercaptoacetate and reduced leukocyte taurine levels constituted additional evidence of decreased intracellular availability of cysteine, i.e. glutathione. Oral supplementation with N-acetylcysteine (5 mg/kg x 3/day) had no effect on acid-base balance, erythrocyte glutathione levels or 5-oxoproline concentrations in plasma and urine. In leukocytes, the glutathione concentrations were increased by 20-30%, whereas the gamma-glutamylcysteine levels were essentially unaltered. In parallel, the urinary excretion of cysteinylglycine was increased and the leukocyte levels and urinary outputs of sulphur amino acids were restored. No side-effects of the treatment were noted. The results indicate that N-acetylcysteine may be of value in increasing the low intracellular glutathione concentrations and cysteine availability in patients with hereditary glutathione synthetase deficiency.

Glutathione synthetase-deficient lymphocytes and acetaminophen toxicity.

Toxic electrophilic metabolites of acetaminophen are detoxified by conjugation with glutathione. Cellular glutathione content of patients with glutathione synthetase deficiency (5-oxoprolinuria) is 10% to 20% of normal. These patients might be at increased risk for acetaminophen toxicity. The hypothesis was tested by challenging lymphocytes from normals and a patient with glutathione synthetase deficiency in vitro with acetaminophen metabolites generated by a mouse hepatic microsomal drug-metabolizing system. For toxicity to be manifested in normal cells, glutathione content had to be depleted to less than 20% of control values at high acetaminophen concentrations (500 and 1,500 micrograms/ml), concentrations similar to blood levels in massive overdose and associated with hepatotoxicity in vivo. The patient's cells had only 14% of normal glutathione content, and exhibited more toxicity at 12.5 micrograms/ml acetaminophen (within the therapeutic range) as normals at maximum concentrations. The in vitro system may be of value in screening drugs potentially hazardous for glutathione synthetase-deficient patients, for exploring the role of glutathione in the detoxification of xenobiotics, and for examining glutathione protective mechanisms in patients with idiosyncratic cytotoxic drug reactions.