Effect of nonsteroidal anti‐inflammatory drugs on glycogenolysis in isolated hepatocytes

Abstract

I E-series prostaglandins have previously been demonstrated to inhibit hormone-stimulated glycogenolysis when added to isolated hepatocytes of the rat. In the present study, the effect of nonsteroidal anti-inflammatory drugs, which inhibit cyclo-oxygenase activity, on glycogenolysis was examined in the hepatocyte model. Ibuprofen (80 gM), indomethacin (501M) and meclofenamate (60 LM) all increased rates ofglycogenolysis when added under basal conditions. In contrast, piroxicam (50 jM) had no effect on glycogenolysis in the hepatocyte system. Concentrations of ibuprofen below 80 gM did not significantly increase rates of glycogenolysis. 2 Ibuprofen (801M) had no effect on glycogenolysis in the presence of 10-5M adrenaline or 5 x 10-7M glucagon, but did increase glycogenolytic rates in the presence of 5 x 10-8M glucagon. 3 Ibuprofen-stimulated glycogenolysis was inhibited by addition of prostaglandin E2 (PGE2). Under conditions where glucagon-stimulated glycogenolysis was inhibited by exogenous PGE2, addition of ibuprofen (80 giM) increased the rate of glycogenolysis.4 Ibuprofen had no effect on basal or glucagon-stimulated hepatocyte adenylate cyclase activity. 5 In conclusion, these results demonstrate that nonsteroidal anti-inflammatory drugs which are carboxylic acids can increase the rate of glycogenolysis in isolated hepatocytes. The high concentrations of drug required to stimulate glycogenolysis, the lack of effect of piroxicam, and the demonstration of stimulation by ibuprofen in the presence of exogenous PGE2 all suggest that the stimulation of glycogenolysis by ibuprofen, indomethacin and meclofenamate is independent ofcyclooxygenase inhibition. These observations are consistent with reports that carboxylic acid nonsteroidal anti-inflammatory drugs can interfere with hepatic intracellular calcium handling.

Feedback-inhibition of glucagon-stimulated glycogenolysis in hepatocyte/kupffer cell cocultures by glucagon-elicited prostaglandin production in kupffer cells

“…Other PGH synthase inhibitors like indomethacin, ibuprofen, and piroxicam also attenuated the inhibition by PGE, of glucagon-stimulated glycogenolysis in hepatocytes (Hespeling, Unpublished data, February, 1995). 34 In addition, indomethacin and ibuprofen stimulated glycogenolysis in hepatocytes. Thus, the mechanism of abolishment by aspirin of the inhibitory action of exogenous PGEz on the glucagon-dependent glycogenolysis remains to be defined.…”

In Vitro Human Liver Model for Toxicity Assessment with Clinical and Preclinical Instrumentation

“…And these higher values were not the result of greater net triglyceride uptake. Thus, the influence of IBU on gluconeogenesis and glycogenolysis was also observed in vivo [43,48,49]and could be the cause of this observation. Notably, there was no albumin content in samples treated with IBU, which may be caused due to the higher net glucose release (and lower availability for albumin synthesis) [41].…”

Structural specificity for prostaglandin effects on hepatocyte glycogenolysis

“…Functional studies also support the conclusion that endogenous PG production by hepatocytes is quantitatively insignificant. Inhibition of any endogenous PG synthesis with non-steroidal anti-inflammatory drugs has no effect on rates of hepatocyte glycogenolysis [34]. Similarly, exogenous arachidonic acid could not reproduce the action of exogenous PGs in the hepatocyte system (Table 6).…”