Aconitase is a sensitive and critical target of oxygen poisoning in cultured mammalian cells and in rat lungs.
The effect of hyperoxia on activity of the superoxide-sensitive citric acid cycle enzyme aconitase was measured in cultured human epithelial-like A549 cells and in rat lungs. Rapid and progressive loss of > 80% of the aconitase activity in A549 cells was seen during a 24-hr exposure to a PO2 of 600 mmHg (1 mmHg = 133 Pa). Inhibition of mitochondrial respiratory capacity correlated with loss of aconitase activity in A549 cells exposed to hyperoxia, and this effect could be mimicked by fluoroacetate (or fluorocitrate), a metabolic poison of aconitase. Exposure of rats to an atmospheric PO2 of 760 mmHg or 635 mmHg for 24 hr caused respective 73% and 61% decreases in total lung aconitase activity. We propose that early inactivation of aconitase and inhibition of the energy-producing and biosynthetic reactions of the citric acid cycle contribute to the sequelae of lung damage and edema seen during exposure to hyperoxia.
Gardner
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PR
Department of Pediatrics, National Jewish Center for Immunology and Respiratory Medicine, Denver, CO 80206.
Nguyen
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DD
White
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CW
D000154:Aconitate Hydratase / Q000037:antagonists & inhibitors* / Q000302:isolation & purification; D000818:Animals; D002259:Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002951:Citrates / Q000494:pharmacology; D005260:Female; D005463:Fluoroacetates / Q000494:pharmacology; D007700:Kinetics; D008168:Lung / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D010100:Oxygen / Q000633:toxicity*; D010101:Oxygen Consumption / Q000187:drug effects; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley
D002951:Citrates; D005463:Fluoroacetates; C007744:fluorocitrate; D002259:Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone; C014815:fluoroacetic acid; D000154:Aconitate Hydratase; D010100:Oxygen