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Glutathione synthetase–deficient lymphocytes and acetaminophen toxicity
Author(s) -
Spielberg Stephen P,
Gordon Gary B
Publication year - 1981
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1038/clpt.1981.9
Subject(s) - glutathione , acetaminophen , toxicity , pharmacology , in vivo , chemistry , detoxification (alternative medicine) , xenobiotic , biochemistry , enzyme , medicine , biology , pathology , microbiology and biotechnology , alternative medicine , organic chemistry
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 <20% of control values at high acetaminophen concentrations (500 and 1,500 µg/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 µg/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. Clinical Pharmacology and Therapeutics (1981) 29, 51–55; doi: 10.1038/clpt.1981.9