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ENZYMIC AND CEREBRAL METABOLIC EFFECTS OF 2‐DEOXY‐ d ‐GLUCOSE
Author(s) -
Horton R. W.,
Meldrum B. S.,
Bachelard H. S.
Publication year - 1973
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.1973.tb05996.x
Subject(s) - 2 deoxy d glucose , carbohydrate metabolism , endocrinology , medicine , d glucose , chemistry , glycolysis , glucose 6 phosphate , metabolism , in vivo , glucose uptake , l glucose , biochemistry , insulin , enzyme , biology , microbiology and biotechnology , islet
—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.