Wg. Bottje et al., PROSTACYCLIN ELEVATION FOLLOWING GLUTATHIONE DEPLETION IN-VIVO - POSSIBLE THRESHOLD DEPENDENCY IN LIVER AND LUNG, Biochemical pharmacology, 46(6), 1993, pp. 1019-1027
The major objective of this study was to determine if a threshold leve
l of glutathione (GSH) depletion is required to elevate plasma prostac
yclin (6-ketoPGF1alpha) in male Sprague-Dawley rats. Rats were treated
i.p. with various doses of phorone, diethyl maleate (DEM), or GSH wit
h and without DEM. Similar maximal depletions of hepatic GSH (to 10% o
f control) and renal GSH (to 50% of control) were observed with DEM an
d phorone, but lung GSH was depleted maximally by only 30% with phoron
e compared with a 70% depletion by DEM. Changes in lung GSH, but not k
idney GSH, were closely correlated with changes in hepatic GSH. 6-Keto
PGF1alpha levels in the lung were 10- to 30-fold higher than in kidney
or liver, and there was a stronger correlation between lung and plasm
a 6-ketoPGF1alpha than with the other two tissues. The increase in lun
g 6-ketoPGF1alpha following GSH depletion did not appear to be due to
a shift in prostaglandin metabolite synthesis since reciprocal changes
in PGE, were not observed; lung PGE, levels were largely unaffected b
y DEM or phorone. Both DEM and phorone elevated plasma 6-ketoPGF1alpha
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-ketoPG
F1alpha by 1.0 mL DEM/kg was attenuated by simultaneous administration
of 2 mmol GSH/kg. The results indicate that the lung may he responsib
le for increases in plasma 6-ketoPGF1alpha following GSH depletion and
that a critical level of GSH depletion in the liver and/or lung may b
e necessary to elevate plasma 6-ketoPGF1alpha levels.