Metabolic Stability of 3‐O‐Methyl‐d‐Glucose in Brain and Other Tissues

Abstract

3-O-Methyl-D-glucose (methylglucose) is often used to study blood-brain barrier transport and the distribution spaces of hexoses in brain. A critical requirement of this application is that it not be chemically converted in the tissues. Recent reports of phosphorylation of methylglucose by yeast and heart hexokinase have raised questions about its metabolic stability in brain. Therefore, we have re-examined this question by studying the metabolism of methylglucose by yeast hexokinase and rat brain homogenates in vitro and rat brain, heart, and liver in vivo. Commercial preparations of yeast hexokinase did convert methylglucose to acidic products, but only when the enzyme was present in very large amounts. Methylglucose was not phosphorylated by brain homogenates under conditions that converted 97% of [U-14C]glucose to ionic derivatives. When [14C]methylglucose, labeled in either the methyl or glucose moiety, was administered to rats by an intravenous pulse or a programmed infusion that maintained the arterial concentration constant and total 14C was extracted from the tissues 60 min later, 97-100% of the 14C in brain, greater than 99% of the 14C in plasma, and greater than 90% of that in heart and liver were recovered as unmetabolized [14C]methylglucose. Small amounts of 14C in brain (1-3%), heart (3-6%), and liver (4-7%) were recovered in acidic products. Plasma glucose levels ranging from hypoglycemia to hyperglycemia had little influence on the degree of this conversion. The distribution spaces for methylglucose were found to be 0.52 in brain and heart and 0.75 in liver.

CEST MRI of 3‐O‐methyl‐D‐glucose on different breast cancer models

“…However, the disadvantage of CEST compared with PET is that in the former modalities the baseline CEST signal should be run while in the PET experiment, the baseline is essentially zero. Both FDG and 3OMG reflect tumor metabolism, but FDG is “trapped” in the cells owing to its phosphorylation while 3OMG is washed out by the kidneys . Thus, the fact that 3OMG is not accumulated in the body allows repetitive measurements in a relatively short time and hence has the advantage of the possibility of monitoring the effects of therapy.…”

Role of Monosaccharide Transport Proteins in Carbohydrate Assimilation, Distribution, Metabolism, and Homeostasis

“…Thus, when transport rate-limiting for 2-DOG uptake and metabolism, measurement of 2-deoxy-D-glucose-6-phosphate accumulation is an accurate reflection of the rate of 2-DOG transport. In contrast, 3-O-methyl-D-glucose is a sugar analog that is transported by GLUT1 but is not phosphorylated by hexokinase (289). In human red cells where metabolic rates are some 3 orders of magnitude slower than transport rates (283), it is possible to measure the kinetics of D-glucose, 2-deoxy-D-glucose and 3-O-methylglucose transport without fear of secondary complications arising from the metabolism of the sugars.…”

Anticonvulsant and proconvulsant actions of 2‐deoxy‐d‐glucose

“…Because many anticonvulsant treatments, including the KD (Bough et al., 2000), can show proconvulsant as well as anticonvulsant properties in different seizure tests (Löscher, 2009), and also because severe glucose deprivation can induce seizures, we utilized models that allow proconvulsant as well as anticonvulsant effects to be detected. For comparison, we studied 3‐O‐methyl‐glucose (3‐MG), which is transported into cells but is not a substrate for brain hexokinase and, therefore, does not inhibit glycolysis (Colby & Romano, 1975; Jay et al., 1990).…”