Kinetic characterization of hexokinase isoenzymes from glioma cells: Implications for FDG imaging of human brain tumors

Quantitative imaging of glucose metabolism of human brain tumors with PET u tilizes 2-[F-18]-fluorodeoxy-D-glucose (FDG) and a conversion factor called the lumped constant (LC), which relates the metabolic rate of FDG to gluco se. Since tumors have greater uptake of FDG than would be predicted by the metabolism of native glucose, the characteristic of tumors that governs the uptake of FDG must be part of the LC. The LC is chiefly determined by the phosphorylation ratio (PR), which is comprised of the kinetic parameters (K m and Vmax) of hexokinase (HK) for glucose as well as for FDG (LC infinity (Km(glc) .Vmax(FDG))/(Km(FDG) . Vmax(glc)). The value of the LC has been es timated from imaging studies, but not validated in vitro from HK kinetic pa rameters. In this study we measured the kinetic constants of bovine and 36B -10 rat glioma HK I (predominant in normal brain) and 36B-10 glioma HK II ( increased in brain tumors) for the hexose substrates glucose, 2-deoxy-D-glu cose (2DG) and FDG. Our principal results show that the KmGlc < KmFDG << Km 2DG and that PR2DG < PRFDG. The FDG LC calculated from our kinetic paramete rs for normal brain, possessing predominantly HK I, would be higher than th e normal brain LC predicted from animal studies using 2DG or human PET stud ies using FDG or 2DG. These results also suggest that a shift from HK I to HK II, which has been observed to increase in brain tumors, would have litt le effect on the value of the tumor LC. (C) 2001 Elsevier Science Inc. All rights reserved.