Studies of Glucocorticoid Enhancement of the Capacity of Hepatocytes to Accumulate Cyclic AMP

Abstract

Pretreatment of cultured rat hepatocytes with dexamethasone markedly enhanced the acute cAMP response to glucagon, isoproterenol or forskolin. The effect of dexamethasone was apparent within 3-6 hr and was maximal after 20-30 hr. The amplification of the cAMP response to glucagon could also be produced by other glucocorticoids, with relative potency dexamethasone much greater than methylprednisolone greater than hydrocortisone. The increased cAMP response was associated with a reduced cAMP phosphodiesterase activity in cell lysates and a reduced effect of the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine in intact cells, indicating that the glucocorticoid pretreatment reduced cAMP degradation. However, the increase in response to glucagon in glucocorticoid-treated cells was relatively larger than the increase in forskolin response and also larger than the decrease in phosphodiesterase activity, suggesting that other factors in addition to down-regulation of phosphodiesterases was responsible for the effect. Cycloheximide abolished the difference in phosphodiesterase activity and cAMP response between dexamethasone-treated and control cells. The results suggest that the glucocorticoids increase the ability of hepatocytes to accumulate cAMP due to protein synthesis-dependent processes which at least in part involve reduced degradation of cAMP.

Receptor/Gene-Mediated Pharmacodynamic Effects of Methylprednisolone on Phosphoenolpyruvate Carboxykinase Regulation in Rat Liver

“…The CS can increase cAMP accumulation in various cell types in vitro (Hege Thoresen et al, 1989;Yingling et al, 1994;Baus et al, 2001). Our results confirmed this phenomenon in vivo and showed its time pattern.…”

Efficacy of short‐term dexamethasone therapy in acute‐on‐chronic pre‐liver failure

“…These results indicated that short‐term dexamethasone therapy was effective in improving the liver function of patients with pre‐ACLF HBV, especially in facilitating the rapid reduction of serum T‐Bil and shortening the course of disease. The mechanisms of dexamethasone treatment are not well clarified, and may be associated with its following roles: (i) to prevent HBV‐induced primary liver injury by inhibiting excessive immune response; (ii) to prevent endotoxin‐induced secondary liver injury by inhibiting the production of oxygen free radicals and cytokines; 22–24 (iii) to prevent cytolysis of ballooned hepatocytes by stabilization of the lysosomal membrane, and inhibiting the production of lysosomal proteases and circulating toxic substances; 24 and (iv) to improve the functional activity of remaining hepatocytes 25,26 …”

“…The mechanisms of dexamethasone treatment are not well clarified, and may be associated with its following roles: (i) to prevent HBV-induced primary liver injury by inhibiting excessive immune response; (ii) to prevent endotoxin-induced secondary liver injury by inhibiting the production of oxygen free radicals and cytokines; [22][23][24] (iii) to prevent cytolysis of ballooned hepatocytes by stabilization of the lysosomal membrane, and inhibiting the production of lysosomal proteases and circulating toxic substances; 24 and (iv) to improve the functional activity of remaining hepatocytes. 25,26 Because of concern about the complications of dexamethasone, it is necessary to determine the indication, course and timing of dexamethasone therapy. As already known, the continuous rapid drop of serum T-Bil is an important marker of liver function improvement and good prognosis, so the decline extent of serum T-Bil can be used as an indicator of response to 5 days of dexamethasone therapy.…”

Beclomethasone Decreases Elevations in Phosphodiesterase Activity in Human T Lymphocytes

“…This group demonstrated that incubation of HTC hepatoma cells with dexamethasone (DEX) for 72 h decreased cAMP hydrolyzing activity of two of the PDE isoenzymes. Further experiments with rat hepatocytes revealed that DEX actually potentiates the cellular cAMP response by specifically decreasing PDE activity [29]and that this effect could be abolished by cycloheximide [30]. Finally, there are data showing that DEX increases PDE 1 activity in rat hepatocytes and that this effect requires both transcription and translation [31].…”