O2-induced changes in lung and storage pool thiols in mice: effect of superoxide dismutase.
Because glutathione (GSH) is an important antioxidant, we hypothesized that changes in lung and systemic availability of GSH and its precursor amino acid, cysteine, are induced by exposure to hyperoxia and that these changes could be modulated by toxic O2 metabolites. In organs and plasma of mice exposed to hyperoxia, we measured GSH and sulfur-containing amino acids (SAAs), the latter by capillary gas chromatography-mass spectrometry. In relatively O2-resistant Swiss-Webster mice, lung GSH increased during O2 exposure, whereas liver GSH (the major storage pool of cysteine) and liver and plasma cysteine all decreased. Pair-feeding studies suggested that nutritional deprivation alone did not cause the decrease in plasma cysteine. In lung, SAAs were not decreased by O2 exposure. In fact, cystathionine increased sixfold, and gamma-cystathionase was not inhibited. These findings suggest that hyperoxia increases transsulfuration pathway activity and that cystathionase rate limits this process in lung. In comparative studies, lung GSH increased in O2-resistant high-CuZn superoxide dismutase (SOD) transgenic mice but not in genetically similar, nontransgenic controls (CBYB/6 x B6D/2) during hyperoxic exposure. In addition, liver GSH and plasma cysteine decreased in nontransgenic control but not in high-SOD mice, whereas lung cystathionine increased similarly in both groups. Thus, superoxide or its secondary products can modulate, at least in part, the changes in cysteine and GSH. Nonetheless, regardless of strain or SOD status, hyperoxic exposure consistently caused thiol and SAA changes, including increased lung cystathionine and oxidized GSH, demonstrating a strong association between these dynamic changes and oxidant stress.
Rusakow
L S
LS
Department of Pediatrics, National Jewish Center for Immunology and Respiratory Medicine, Denver, Colorado 80262.
White
C W
CW
Stabler
S P
SP
D000596:Amino Acids / Q000378:metabolism; D000603:Amino Acids, Sulfur / Q000378:metabolism; D000818:Animals; D003542:Cystathionine gamma-Lyase / Q000378:metabolism; D004591:Electrophoresis, Polyacrylamide Gel; D005260:Female; D008401:Gas Chromatography-Mass Spectrometry; D005978:Glutathione / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D010100:Oxygen / Q000494:pharmacology*; D010641:Phenotype; D013438:Sulfhydryl Compounds / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000235:genetics / Q000494:pharmacology*
D000596:Amino Acids; D000603:Amino Acids, Sulfur; D013438:Sulfhydryl Compounds; D013482:Superoxide Dismutase; D003542:Cystathionine gamma-Lyase; D005978:Glutathione; D010100:Oxygen