ENZYMIC AND CEREBRAL METABOLIC EFFECTS OF 2‐DEOXY‐d‐GLUCOSE

Abstract

—The time course of effects of 2‐deoxy‐d‐glucose on cerebral glucose metabolism has been studied in vivo and the inhibitory actions of 2‐deoxy‐d‐glucose and 2‐deoxy‐d‐glucose‐6‐phosphate on cerebral glycolytic enzymes in vitro. Mice were given 2‐deoxy‐d‐glucose 3 g/kg intraperitoneally. Blood 2‐deoxy‐d‐glucose/glucose ratio was 2–3 from 5 to 30 min after injection, the hyperglycaemic response to 2‐deoxy‐d‐glucose having been suppressed with propranolol. Maximal cerebral 2‐deoxy‐d‐glucose uptake observed was 1μ11 μmol/g/min between 5 and 10 min after injection. At 10 min brain concentrations of 2‐deoxy‐d‐glucose and 2‐deoxy‐d‐glucose‐6‐phosphate were 5·82 and 3·12 μmol/g. Analysis of the fate of d‐[U‐14 C] glucose given subcutaneously 5 min before death showed that glucose uptake was reduced to 40–60 per cent of control from 5 to 30 min after 2‐deoxy‐d‐glucose. However brain glucose concentration rose three to five‐fold 20–30 min after 2‐deoxy‐d‐glucose. The majority of glucose entering the brain after 10 min of 2‐deoxy‐d‐glucose treatment was recovered as glucose. Conversion of brain glucose to other acid soluble components was reduced to 1/3 at 10 min and 1/5 at 20–30 min. Glucose‐6‐phosphate concentration rose from 5 min onwards and was maintained at twice control concentration from 10–30 min. However, because of the rapid entry of 2‐deoxy‐d‐glucose and its conversion to 2‐deoxy‐d‐glucose‐6‐phosphate, the 2‐deoxy‐d‐glucose 6‐P/glucose 6‐P ratio was between 19 and 32. Brain adenosine triphosphate concentration did not change, creatine phosphate concentration fell after 25 min. Measurement of enzyme activities in cerebral homogenates (using 1 mivs substrate concentration) showed that hexokinase (EC 2.7.1.1) was 40 per cent inhibited by 5 m m‐deoxy‐d‐glucose (but not by 2‐deoxy‐d‐glucose 6‐P). Glucose 6‐P dehydrogenase (EC 1.1.1.49), 6‐phosphogluconate dehydrogenase (EC 1.1.1.43) and phosphoglucomutase (EC 2.7.5.1) were not affected by either 2‐deoxy‐d‐glucose (5 m m) or 2‐deoxy‐d‐glucose 6‐P (5 or 20 m m). Hexose‐phosphate isomerase (EC 5.3.1.9) was 70 per cent inhibited by 20 m m‐d‐deoxy‐d‐glucose 6‐P. Phosphofructokinase (EC 2.7.1.11) was inhibited by 17 per cent by 2‐deoxy‐d‐glucose 6‐P (20 m m). During the initial impairment of cerebral function by 2‐deoxy‐d‐glucose there is competitive inhibition of glucose transport into the brain; later, glycolysis is more powerfully depressed by the inhibition of isomerase produced by the high intracerebral concentration of 2‐deoxyglucose‐6‐phosphate.