DEXAMETHASONE INDUCES RESISTANCE TO THE LETHAL CONSEQUENCES OF ELECTRON-TRANSPORT INHIBITION IN CULTURED-HEPATOCYTES

Pretreatment of cultured rat hepatocytes with 1 mu M dexamethasone protected against cell killing by 5 mu M rotenone and 1 mM cyanide, Simultaneous treatment (no pretreatment) was ineffective, as was pretreatment with 10 mu M Of sex hormones or the mineralocorticoid aldosterone, Protection by dexamethasone was blocked by 10 mu M Of glucocorticoid receptor antagonist, RU486, and by 1 mu M of the inhibitor of protein synthesis, cycloheximide, Cells pretreated with dexamethasone for 6, 12, and 18 h showed increasing degrees of protection, Pretreatment with dexamethasone had no effect on either the decline of cellular ATP or the loss of the mitochondrial membrane potential, In addition, dexamethasone did not prevent the mitochondrial permeability transition, By contrast, dexamethasone prevented the increased release of [H-3]arachidonic acid from phospholipids produced by cyanide. These data describe an inductive effect of dexamethasone in protecting cultured hepatocytes against inhibition of electron transport by rotenone and cyanide, It is concluded that pretreatment with dexamethasone prevents cell killing by inhibiting a mechanism that couples the mitochondrial permeability transition to the accelerated degradation of plasma membrane phospholipids. (C) 1995 Academic Press, Inc.