L-2-[(13)C]oxothiazolidine-4-carboxylic acid: a probe for precursor mobilization for glutathione synthesis.
L-2-oxothiazolidine-4-carboxylic acid (OTZ), a 5-oxoproline analog, is metabolized by 5-oxoprolinase and converted to cysteine, the rate-limiting amino acid for GSH synthesis, with the release of CO(2). [(13)C]OTZ (1.5 mg/kg) was used in 12 healthy men and women (ages 23-73 yr) to indirectly assess precursor mobilization for GSH synthesis when stores were reduced by 2 g acetaminophen. Expired breath samples were analyzed for (13)CO(2), and results were analyzed using noncompartmental and two-compartment open minimal models. Results show an increase in (13)C excretion (higher OTZ hydrolysis) when GSH stores were reduced and 5-oxoprolinase substrate utilization patterns, consequently, were altered (P < 0. 01). A metabolic rate index (MRI) of the OTZ probe was found to be significantly higher after reduction of GSH content by acetaminophen (P < 0.05). The difference in adaptive capacity (difference between control and postacetaminophen metabolic rate indexes) was two times as large in the young than the old subjects (P < 0.01). These data support the use of [(13)C]OTZ as a probe to identify individuals who may be at risk for low GSH stores or who have an impaired capacity to synthesize GSH.
Fukagawa
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University of Vermont/Fletcher Allen Health Care General Clinical Research Center and Department of Medicine, Burlington, Vermont 05405-0068, USA. nfukugawa@zoo.uvm.edu
Hercules
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Ajami
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D000082:Acetaminophen / Q000494:pharmacology; D000328:Adult; D000368:Aged; D001944:Breath Tests; D002153:Calorimetry, Indirect; D002245:Carbon Dioxide / Q000378:metabolism; D003545:Cysteine / Q000378:metabolism*; D005260:Female; D005978:Glutathione / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D006801:Humans; D007700:Kinetics; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D011355:Prodrugs / Q000378:metabolism*; D011761:Pyrrolidonecarboxylic Acid; D013844:Thiazoles; D053778:Thiazolidines
D011355:Prodrugs; D013844:Thiazoles; D053778:Thiazolidines; D002245:Carbon Dioxide; D000082:Acetaminophen; D005978:Glutathione; D003545:Cysteine; D011761:Pyrrolidonecarboxylic Acid; C029536:2-oxothiazolidine-4-carboxylic acid