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.
D000082:Acetaminophen / Q000009:adverse effects* / Q000378:metabolism; D000818:Animals; D002675:Child, Preschool; D004353:Drug Evaluation, Preclinical; D005978:Glutathione / Q000097:blood; D005981:Glutathione Synthase / Q000172:deficiency*; D006801:Humans; D066298:In Vitro Techniques; D008658:Inactivation, Metabolic; D008214:Lymphocytes / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D010453:Peptide Synthases / Q000172:deficiency*
D000082:Acetaminophen; D010453:Peptide Synthases; D005981:Glutathione Synthase; D005978:Glutathione