Effect of endotoxin and glucocorticoid pretreatment on hexose monophosphate shunt activity in rat liver.

The acceleration of glycolysis by the Embden-Meyerhof pathway (EMP) in endotoxic and septic states and its counteraction by glucocorticoids has been demonstrated by past research. Although the glycolytic contribution of the hexose monophosphate (HMP) shunt is minor, its response during endotoxemia, if similar to that of EMP, could be theoretical interest, Fasted male rats (150-260 gm) were sacrificed at 5 hr after IV injection of E coli endotoxin in dosages of 2 or 3 mg/100 gm rat weight: LD50 (Nm= 15). A second group received 1 mg dexamethasone (DMS) IV per 100 gm rat weight simultaneously with endotoxin (N = 15). Livers were homogenized in 0.25 M cold sucrose and centrifuged at 15,000 g for 20 min. Specific activity of glucose-6-phosphate dehydrogenase (G6PDH) in control livers (N = 17) was 7.1 nmoles of substrate consumed per min/mg biuret protein. Endotoxin raised G6PDH activity by 49% to 10.64 units, and the endotoxin-DMS-protected group was 6.0 units. Levels of 6-phosphogluconate (6PG) were also measured in frozen liver biopsies from similar groups of rats. Liver 6PG concentrations of control (N = 15), endotoxic (N = 15), and endotoxified-DMS-treated (N = 9) groups were 22.5, 14.3, and 17.6 nmoles/gm wet tissue, respectively. The data indicate a significant 36% acceleration in 6PG consumption during endotoxemia, which is not blocked by DMS. The cofactor, nicotinamide adenine dinucleotide phosphate (NADP), decreased significantly by 18% from the control level of 152 nmoles/gm liver (N = 9) during endotoxemia, and this fall was not corrected by DMS. In a small group (N = 6), sedoheptulose-7-phosphate declined from the control value of 76 nmoles/gm wet liver by 38% after endotoxification. It is concluded that endotoxin stimulates G6PDH, the initial enzyme of the HMP pathway, and accelerates consumption of several intermediates, Glucocorticoid prevents the enzyme activity increase but does not restore 6PC and NADP concentrations to normal levels, suggesting that different enzyme sites along the HMP shunt may have unequal responses to DMS.