Biochemical Mechanisms of Action

The physiological and pharmacological properties of caffeine cannot be explained by a single biochemical mechanism. Three principal hypotheses have been investigated to explain the diverse actions of caffeine.

The first biochemical effect described was the inhibition of phosphodiesterase, the enzyme that catalyzes the breakdown of cyclic adenosine 3',5'-phosphate (cAMP). Caffeine was shown to increase cAMP concentrations in various tissues. This inhibition occurs at large concentrations (millimolar range) and is of limited importance with regard to the physiological effects of caffeine at levels at which it is normally consumed.

Calcium translocation is the second mechanism frequently suggested from experiments using skeletal muscles. However, high concentrations of caffeine are also necessary to modify intracellular calcium ion storage.

In the plasma, increased levels of ^-endorphin, epinephrine, norepinephrine, corticosterone, ACTH, renin, and angiotensin I and decreased levels of growth hormone, thyroxine, triiodothyronine, and thyrotropin were reported with high caffeine doses. The mechanisms responsible for these various effects are largely unknown, and the mediation of adenosine receptors is suggested. The antagonism of benzodiazepine at the receptor level is observed at lower caffeine concentrations (0.5-0.7mM) than those required for phosphodiesterase inhibition.

The third mechanism, antagonism of the endogenous adenosine, is the most plausible mode of action because caffeine exerts its antagonism at micromolar levels. Its main metabolite, paraxanthine, is as potent as caffeine in blocking adenosine receptors. Caffeine is more potent at A2A receptors and less potent at A3 receptors compared to A1 and A2B receptors. An upregulation of adenosine receptor is the postulated biochemical mechanism of caffeine tolerance.

Adenosine receptor antagonism appears to be the mechanism that explains most of the effects of caffeine on CNS activity, intestinal peristalsis, respiration, blood pressure, lipolysis, catecholamine release, and renin release. However, some effects, such as opiate antagonism or effects that are similar to those of adenosine, must be mediated by other mechanisms, such as the potentiation by caffeine of inhibitors of prostaglandin synthesis.

See also: Brain and Nervous System. Diabetes Mellitus: Etiology and Epidemiology. Energy: Balance; Requirements. Exercise: Beneficial Effects; Diet and Exercise. Sports Nutrition. Tea.

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