DEFICIENT GLUTATHIONE-PEROXIDASE ACTIVITY IN PREECLAMPSIA IS ASSOCIATED WITH INCREASED PLACENTAL PRODUCTION OF THROMBOXANE AND LIPID PEROXIDES

OBJECTIVE: Thromboxane and lipid peroxide levels are abnormally increased in preeclamptic placentas. The cause of this increase is not known. Peroxides stimulate prostaglandin H-2 synthase to increase thromboxane and oxygen radicals, which increase lipid peroxides. Glutathione peroxidase inactivates peroxides, thereby decreasing peroxide stimulation of prostaglandin H synthase. If glutathione peroxidase activity were deficient, then peroxides could increase, leading to increased stimulation of prostaglandin H synthase, resulting in increased production of thromboxane and lipid peroxides. The following study tested this hypothesis. STUDY DESIGN: Placental tissues from 11 normal and 11 preeclamptic women were immediately frozen in liquid nitrogen after delivery. One gram of tissue from each placenta was homogenized for analysis. Placental tissues were also obtained from six normal pregnancies for incubation with a glutathione peroxidase inhibitor, N-ethylmaleimide. Samples were analyzed for glutathione peroxidase activity, lipid peroxides by hydrogen peroxide equivalents, thromboxane by thromboxane B2, and prostacyclin by 6-keto-prostaglandin F1alpha. RESULTS: Glutathione peroxidase activity was significantly lower in preeclamptic than in normal placentas (9.41 +/- 0.05 vs 13.41 +/- 0.63 units/gm, p < 0.001, mean +/- SE). Lipid peroxides and thromboxane were significantly higher in preeclamptic than in normal placentas (hydrogen peroxide equivalents 4.23 +/- 0.32 vs 2.84 +/- 0.27 mumol/gm, p < 0.01; thromboxane B2 215 +/- 31 vs 138 +/- 15 ng/gm, p < 0.05), whereas prostacyclin was significantly lower (6-keto-prostaglandin F1alpha 23.3 +/- 2.2 vs 41.6 +/- 6.0 ng/gm, p < 0.01). Inhibition of glutathione peroxidase activity in normal placentas resulted in a dose-response increase in placental production of both lipid peroxides and thromboxane without affecting prostacyclin, so the ratio of thromboxane to prostacyclin increased progressively with inhibition of glutathione peroxidase. CONCLUSIONS: Glutathione peroxidase activity is significantly lower, and lipid peroxides and thromboxane are significantly higher, in preeclamptic placentas compared with normal placentas. Inhibition of glutathione peroxidase activity in normal placentas results in significantly increased production of lipid peroxides and thromboxane and an increase in the thromboxane to prostacyclin ratio. We speculate that in normal placentas, glutathione peroxidase limits prostaglandin H synthase activity by reducing the amount of peroxide present, thus reducing peroxide stimulation of prostaglandin H synthase. In preeclampsia deficient glutathione peroxidase activity results in increased peroxide levels leading to increased stimulation of prostaglandin H synthase, which results in increased production of lipid peroxides and thromboxane.