Endotoxin treatment inhibits glucocorticoid induction of hepatic enzymes at a late induction step.

Bacterial endotoxin inhibits the glucocorticoid induction of several hepatic enzymes including phosphoenolpyruvate carboxykinase (PEPCK). Experiments were performed to elucidate the mechanism of this inhibition by examination of the early events in the glucocorticoid induction process. At a dose of endotoxin 2-to 10-fold greater than that required to inhibit the induction of PEPCK activity, no effect on the entry of glucocorticoids into hepatocytes or their ability to form complexes with glucocorticoid receptors could be measured. Binding data showed no effect of endotoxin treatment on the association or dissociation kinetics of the steroid-receptor binding reaction. Scatchard analysis revealed no effect on the affinity and number of hepatic glucocorticoid receptor binding sites, indicating that down-regulation of receptors is not responsible for inhibition of induction. Finally, activation of receptor complexes was unaffected as well by endotoxin treatment. We conclude from these data that endotoxin does not act at the early events in the glucocorticoid induction process and must therefore intervene at a subsequent step.