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OtherDRUG METABOLISM AND DISPOSITION

The Effect of Caffeine and Caffeine Analogs on Rat Liver Phosphorylase a Activity

Nacide Ercan-Fang and Frank Q. Nuttall
Journal of Pharmacology and Experimental Therapeutics March 1997, 280 (3) 1312-1318;
Nacide Ercan-Fang
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Frank Q. Nuttall
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Abstract

Liver phosphorylase a is stimulated by adenosine monophosphate. It is inhibited by adenosine diphosphate, adenosine triphosphate and glucose. Using these effectors as well as other potential in vivo effectors at concentrations approximating those present in hepatocytes, we previously reported that the net effect was nil, i.e., at estimated in vivo concentration, the inhibitors neutralized the stimulatory effect of adenosine monophosphate in a phosphorylase apreparation. In addition, a concentration dependent inhibition by glucose was not present. Therefore, we were interested in determining if addition of caffeine, an inhibitor that synergizes with glucose, would result in a reduction in activity in the presence of the other effectors and restore regulation by physiological concentrations of glucose. The effect of xanthine and xanthine analogs also were studied. Purified liver phosphorylase a was used. Activity was measured in the direction of glycogenolysis at 37°, pH 7.0 and under initial rate conditions. Caffeine (1 mM) was added to individual and various combinations of other effectors. The interactions among the potential in vivo effectors when caffeine was present were complex. However, when caffeine was present glucose again regulated activity. This most likely was due to a synergistically facilitated reduction in binding affinity for AMP by caffeine and glucose. Theophylline and adenosine did not inhibit activity but reduced AMP stimulation and facilitated glucose inhibition. Xanthine and the other xanthine derivatives all strongly inhibited activity and the inhibition was independent of other effectors.

Footnotes

  • Send reprint requests to: Dr. Frank Q. Nuttall, Minniapolis VA Medical Center, One Verterans Drive (111G), Minneapolis, MN 55417.

  • ↵1 This study was supported by Merit Review Research Funds from the Department of Veterans Affairs and Grant DK43018 from the National Institutes of Health.

  • Abbreviations:
    AMP
    adenosine monophosphate
    ADP
    adenosine diphosphate
    ATP
    adenosine triphosphate
    PI
    inorganic phosphate
    UDP-glucose
    urindine dephosphoglucose
    NMR
    nuclear magnetic resonance
    • Received June 24, 1996.
    • Accepted November 6, 1996.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 280, Issue 3
1 Mar 1997
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OtherDRUG METABOLISM AND DISPOSITION

The Effect of Caffeine and Caffeine Analogs on Rat Liver Phosphorylase a Activity

Nacide Ercan-Fang and Frank Q. Nuttall
Journal of Pharmacology and Experimental Therapeutics March 1, 1997, 280 (3) 1312-1318;

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OtherDRUG METABOLISM AND DISPOSITION

The Effect of Caffeine and Caffeine Analogs on Rat Liver Phosphorylase a Activity

Nacide Ercan-Fang and Frank Q. Nuttall
Journal of Pharmacology and Experimental Therapeutics March 1, 1997, 280 (3) 1312-1318;
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