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

Pretreatment of cultured rat hepatocytes with 1 mu M dexamethasone pro tected against cell killing by 5 mu M rotenone and 1 mM cyanide, Simul taneous treatment (no pretreatment) was ineffective, as was pretreatme nt with 10 mu M Of sex hormones or the mineralocorticoid aldosterone, Protection by dexamethasone was blocked by 10 mu M Of glucocorticoid r eceptor antagonist, RU486, and by 1 mu M of the inhibitor of protein s ynthesis, 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 t he loss of the mitochondrial membrane potential, In addition, dexameth asone did not prevent the mitochondrial permeability transition, By co ntrast, dexamethasone prevented the increased release of [H-3]arachido nic acid from phospholipids produced by cyanide. These data describe a n 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 killin g by inhibiting a mechanism that couples the mitochondrial permeabilit y transition to the accelerated degradation of plasma membrane phospho lipids. (C) 1995 Academic Press, Inc.