Prostacyclin elevation following glutathione depletion in vivo: Possible threshold dependency in liver and lung

Abstract

The major objective of this study was to determine if a threshold level of glutathione (GSH) depletion is required to elevate plasma prostacyclin (6-ketoPGF 1α) 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-KetoPGF 1α 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- ketoPGF 1α than with the other two tissues. The increase in lung 6-ketoPGF 1α following GSH depletion did not appear to be due to a shift in prostaglandin metabolite synthesis since reciprocal changes in PGE 2 were not observed; lung PGE 2 levels were largely unaffected by DEM or phorone. Both DEM and phorone elevated plasma 6-ketoPGF 1α 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-ketoPGF 1α 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-ketoPGF 1α following GSH depletion and that a critical level of GSH depletion in the liver and/or lung may be necessary to elevate plasma 6-ketoPGF 1α levels.