Prostacyclin elevation following glutathione depletion in vivo. Possible threshold dependency in liver and lung.
The major objective of this study was to determine if a threshold level of glutathione (GSH) depletion is required to elevate plasma prostacyclin (6-ketoPGF1 alpha) in male Sprague-Dawley rats. Rats were treated i.p. with various doses of phorone, diethyl maleate (DEM), or GSH with and without DEM. Similar maximal depletions of hepatic GSH (to 10% of control) and renal GSH (to 50% of control) were observed with DEM and phorone, but lung GSH was depleted maximally by only 30% with phorone compared with a 70% depletion by DEM. Changes in lung GSH, but not kidney GSH, were closely correlated with changes in hepatic GSH 6-KetoPGF1 alpha levels in the lung were 10- to 30-fold higher than in kidney or liver, and there was a stronger correlation between lung and plasma 6-ketoPGF1 alpha than with the other two tissues. The increase in lung 6-ketoPGF1 alpha following GSH depletion did not appear to be due to a shift in prostaglandin metabolite synthesis since reciprocal changes in PGE2 were not observed; lung PGE2 levels were largely unaffected by DEM or phorone. Both DEM and phorone elevated plasma 6-ketoPGF1 alpha but the magnitude of increase for DEM (5- to 6-fold) was much greater than the 2-fold increase for phorone. The increase in plasma 6-ketoPGF1 alpha by 1.0 mL DEM/kg was attenuated by simultaneous administration of 2 mmol GSH/kg. The results indicate that the lung may be responsible for increases in plasma 6-ketoPGF1 alpha following GSH depletion and that a critical level of GSH depletion in the liver and/or lung may be necessary to elevate plasma 6-ketoPGF1 alpha levels.
Bottje
W G
WG
Department of Animal and Poultry Sciences, University of Arkansas, Fayetteville 72701.
Graupner
W G
WG
Enkvetchakul
B
B
Allen
K G
KG
D015121:6-Ketoprostaglandin F1 alpha / Q000097:blood / Q000378:metabolism; D000818:Animals; D015232:Dinoprostone / Q000378:metabolism; D011464:Epoprostenol / Q000097:blood / Q000378:metabolism*; D005978:Glutathione / Q000172:deficiency* / Q000494:pharmacology; D007659:Ketones / Q000494:pharmacology; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008168:Lung / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008298:Maleates / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
D007659:Ketones; D008298:Maleates; D015121:6-Ketoprostaglandin F1 alpha; C018637:phorone; D011464:Epoprostenol; C014476:diethyl maleate; D005978:Glutathione; D015232:Dinoprostone