Lung mitochondrial function following oxygen exposure and diethyl maleate-induced depletion of glutathione.
Diethyl maleate (DEM) pretreatment has previously been shown to result in a transient depletion of lung glutathione and an associated decrease of the time to the onset of rat mortality resulting from exposures to 100% oxygen in vivo. The effects of oxygen exposure on mitochondrial energy metabolism were assessed by measurements of ADP-stimulated rates of O2 utilization by lung homogenates prepared from untreated and DEM-treated rats following 4 and 24 hr of exposure to either air or 100% oxygen. Twenty-four hours of oxygen exposure of untreated rats resulted in significant decreases in lung homogenate ADP-stimulated rates of respiration supported by the substrates, pyruvate, isocitrate, and alpha-ketoglutarate. No changes were observed in succinate-supported respiration, indicating that oxygen exposure appears to adversely affect NAD-linked rather than FAD-linked pathways of mitochondrial energy metabolism. The decreased lung mitochondrial glutathione, observed 4 hr following DEM treatment, returned to normal levels following 24 hr of air and oxygen exposure. No effects of glutathione depletion were observed on ADP-stimulated rates of respiratory activity 4 hr following DEM treatment. The DEM-induced transient depletion of glutathione also did not result in any additional detrimental effects on mitochondrial respiratory activity following 24 hr of oxygen exposure in vivo. These results suggested that transient mitochondrial depletion of glutathione does not accelerate the oxygen-induced impairment of mitochondrial energy metabolism. The onset of mortality associated with DEM-pretreatment might therefore result from a failure of glutathione-dependent cytosolic protective mechanisms, rather than from an increased rate of oxygen-induced mitochondrial damage.
Bassett
D J
DJ
Department of Environmental Health Sciences, Johns Hopkins University School of Hygiene and Public Health, Baltimore, Maryland 21205.
Reichenbaugh
S S
SS
D000244:Adenosine Diphosphate / Q000378:metabolism; D000818:Animals; D005978:Glutathione / Q000032:analysis*; D066298:In Vitro Techniques; D008168:Lung / Q000737:chemistry*; D008297:Male; D008298:Maleates / Q000494:pharmacology; D008928:Mitochondria / Q000737:chemistry / Q000187:drug effects*; D010100:Oxygen / Q000633:toxicity; D010101:Oxygen Consumption; D051381:Rats; D011919:Rats, Inbred Strains
D008298:Maleates; D000244:Adenosine Diphosphate; C014476:diethyl maleate; D005978:Glutathione; D010100:Oxygen