Impaired synthesis of lipoxygenase products in glutathione synthetase deficiency.
Glutathione synthetase deficiency (GSD) is an inborn error of glutathione (GSH) metabolism leading to a generalized intracellular GSH deficiency. Because GSH is required for leukotriene C4 (LTC4) synthesis, we studied synthesis and metabolism of several lipoxygenase products in two patients with GSD by radio-HPLC, UV spectrophotometry, and enzyme immunoassays. In both patients, LTC4 synthesis was significantly decreased in calcium ionophore-stimulated neutrophils (up to 0.4 ng/10(6) cells; controls, 5.0 +/- 0.9) and monocytes (up to 3.6 ng/10(6) cells; controls, 30.2 +/- 3.3). LTB4 synthesis was about seven times higher in GSD cells compared with controls, whereas synthesis of other 5-, 12-, and 15-lipoxygenase products and prostaglandin E2 was not affected. Neutrophils and monocytes from both patients showed a marked reduction in capacity to form [3H]LTC4 from [3H]LTA4 (9-14% of control values). Urinary LTE4 was finally found to be 50-fold lower in GSD, reflecting a decreased synthesis of cysteinyl LT in vivo. GSD may serve as a unique model for the linkage between LT synthesis and GSH metabolism in vivo.
Mayatepek
E
E
University Children's Hospital, Heidelberg, Germany.
Hoffmann
G F
GF
Carlsson
B
B
Larsson
A
A
Becker
K
K
D000001:Calcimycin / Q000494:pharmacology; D002675:Child, Preschool; D004912:Erythrocytes / Q000378:metabolism; D005260:Female; D005978:Glutathione / Q000097:blood; D005981:Glutathione Synthase / Q000172:deficiency*; D006801:Humans; D066298:In Vitro Techniques; D007223:Infant; D017572:Leukotriene A4 / Q000097:blood; D017997:Leukotriene C4 / Q000097:blood; D017999:Leukotriene E4 / Q000652:urine; D008084:Lipoxygenase / Q000378:metabolism*; D008297:Male; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D013438:Sulfhydryl Compounds / Q000097:blood
D017572:Leukotriene A4; D013438:Sulfhydryl Compounds; D017997:Leukotriene C4; D000001:Calcimycin; D017999:Leukotriene E4; D008084:Lipoxygenase; D005981:Glutathione Synthase; D005978:Glutathione