EFFECTS OF 6-DEOXY-6-FLUORO-D-GLUCOSE 403 



It is very interesting that the atrial depression is completely unassoci- 

 ated with demonstrable changes in the membrane electrical characteristics 

 (E. Ruiz-Petrich). 2-DG at 10 mM depresses the contractile tension around 

 50% at 20-30 min under the conditions of these experiments, glucose being 

 present, but there are no changes at all of the resting potential, the action 

 potential magnitude, or the rates of depolarization and repolarization. The 

 addition of 5 mM pyruvate rapidly stopped the progression of the contractile 

 depression and allowed slight recovery, again without detectable altera- 

 tions of the membrane characteristics. 2-DG is the only inhibitor with which 

 we have worked that is able to affect the contractile processes so selectively, 

 all other inhibitors decreasing the action potential duration to varying 

 degrees and producing other correlated changes in the potentials. If 2-DG 

 acts here by reducing the utilization of glucose or glycogen, these results 

 would point to a close relation between the contractile process and some as- 

 pect of glycolysis other than the generation of ATP. It has also been shown 

 that atrial K+ influx and efflux are only very slightly altered by 11 mM 

 2-DG, and that intracellular K+ is unchanged over a period during which 

 the contractile activity is depressed 50% (Chin, 1963). 



EFFECTS OF 6-DEOXY-6-FLUORO-D-GLUCOSE 

 ON METABOLISM 



Modification of hexoses at the 6-position should interfere with their 

 phosphorylation by hexokinase, and hence any inhibition of glucose metab- 

 olism observed would probably not be exerted beyond the hexokinase step. 

 Thus inhibition produced by 6-substituted sugars should be simpler than 

 inhibition by 2-substituted sugars, which can be phosphorylated and may 

 block at several sites. Brooks et al. (1961) compared 6-deoxy-D-glucose 

 with 2-DG on the oxidation of glucose-u-C^* by various tissues and found 

 it to be somewhat less potent. When glucose is 10 mM and 6-DG is 30 mM, 

 the inhibitions of C^'^Og formation are 43% for adipose tissue, 23% for 

 kidney, and 19% for diaphragm. The inhibition in adipose tissue is reversed 

 by increasing glucose concentration and appears to be competitive. 6-DG 

 is not metabolized by adipose tissue and no C^^Oa arises from 6-DG-u-C^^. 

 The site of inhibition was considered to be either the membrane transport 

 system or hexokinase. It has been found that galactose transport across 

 the intestine is inhibited by 6-DG (47% at 5 mM) and that the transport of 

 6-DG is depressed by glucose (Wilson et al., 1960). 



The replacement of the 6-0II group with fluorine to give 6-deoxy-6- 

 fluoro-D-glucose (6-DFG) leads, as expected, to an interesting inhibitor 

 of glucose utilization. The original idea was apparently to produce a gly- 

 colytic inhibitor with fluorine analogous to the cycle inhibitor fluoroacetate. 

 The initial work was done by Blakley and Boyer (1955) at Minnesota; they 



