Dexamethasone induces resistance to the lethal consequences of electron transport inhibition in cultured hepatocytes.
Pretreatment of cultured rat hepatocytes with 1 microM dexamethasone protected against cell killing by 5 microM rotenone and 1 mM cyanide. Simultaneous treatment (no pretreatment) was ineffective, as was pretreatment with 10 microM of sex hormones or the mineralocorticoid aldosterone. Protection by dexamethasone was blocked by 10 microM of glucocorticoid receptor antagonist, RU486, and by 1 microM 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 [3H]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.
Pastorino
J G
JG
Department of Pathology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
Wilhelm
T J
TJ
Glascott
P A
PA
Kocsis
J J
JJ
Farber
J L
JL
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D003486:Cyanides / Q000633:toxicity; D003513:Cycloheximide / Q000494:pharmacology; D003907:Dexamethasone / Q000494:pharmacology*; D004579:Electron Transport / Q000187:drug effects*; D006868:Hydrolysis; D008099:Liver / Q000187:drug effects* / Q000378:metabolism*; D015735:Mifepristone / Q000494:pharmacology; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism; D010539:Permeability / Q000187:drug effects; D010743:Phospholipids / Q000378:metabolism; D014176:Protein Biosynthesis; D051381:Rats; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D012402:Rotenone / Q000633:toxicity
D003486:Cyanides; D010743:Phospholipids; D011965:Receptors, Glucocorticoid; D012402:Rotenone; D015735:Mifepristone; D003907:Dexamethasone; D000255:Adenosine Triphosphate; D003513:Cycloheximide