The Metabolism of Caffeine
I am getting very, very excited about the therapeutic uses of caffeine and its metabolites.
One of the members posted this review article on caffeine metabolism to the discussion group. It can be read online.
I looked around PubMed for a newer article and found one. I paid my $35 and found that this article was worth its weight in gold.
This is the story.
Caffeine is almost 100% bioavailable. It is readily absorbed into the blood from both the stomach and intestinal tract. It does not bind blood proteins, such as albumin, which would inhibit its biological effectiveness. Caffeine is hydrophobic which means it readily crosses the membranes of all cells in the body. It has total access to the brain.
Its half life in the blood is 2.5 to 10 hours, depending on many factors. The CYP1A2 enzyme in the liver degrades caffeine into 25 different metabolites. The major metabolites of caffeine are theophylline, a common asthma treatment drug, and paraxanthine.
Smoking activates the CYP protein, thereby DECREASING the half life of caffeine in the blood. Oral contraceptives, on the other hand, decrease the activity of the CYP protein, thereby INCREASING the half life of caffeine in the blood. Alcohol decreases the activity of CYP, which increases the half life of caffeine in the blood. Age is not a factor in CYP activity in the liver.
The 50% inhibitory doses of caffeine and its major metabolites on the four adenosine receptors are as follows. The figures are in microM concentrations.
A1
Caffeine 33.8 (28-39), Theophylline 8.9 (6.5-14), Paraxanthine 15.8 (4.5-34)
A2A
Caffeine 12.3 (8-14.8), Theophylline 7.9 (6.3-10), Paraxanthine 5.3 (3.8-6.9)
A2B
Caffeine 15.5 (9.3-21.8), Theophylline 4.8 (3.9-5.8), Paramanthine 5.5 (5.1-5.8)
A3
Caffeine, Theophylline and Paramarthine all in excess of 100 microM.
These inhibitory concentrations were derived in CHO or chinese hamster ovary cells that had been genetically modified to express human adenosine receptors. This is an important point which will be discussed later.
It is quite obvious that the major metabolites of caffeine are also extremely active as inhibitors of adenosine receptors. In fact, they are more active than caffeine in inhibiting the activity of the A1, A2A and A2B receptors.
One 150 ml cup of cofee (1/2 measuring cup) can increase the plasma level of caffeine to 5-10 microM. 5-6 cups of coffee, which the authors consider a moderate level of intake, can increase the plasma level to 50-100 microM. Caffeine does not generate any toxic symptoms until the plasma level exceeds 200 microM.
The more coffee that is consumed on a daily basis, the longer the half life of caffeine in the blood. This is a common observation with the use of many drugs. The CYP enzyme becomes saturated at doses in excess of 100 microM. So the half life of caffeine in the blood increases accordingly.
In previous essays, we have cited evidence that a 10microM dose of caffeine 50% inhibits the activity of the adenosine A2A receptor in lymphoid cells. This results in the reactivation of the entire immune system. This inhibitory concentration conforms to the data presented above.
In the "Big Momma" article in this series, caffeine was shown to be able to inhibit the synthesis of VEGF, HIF-1 and IL-8 in HUMAN colon cancer cells. The 50% effective dose was 10 microM. Only the A2B and A3 receptors are involved in this inhibition.
Yet according to the data presented above, doses in excess of 100 microM are necessary to inhibit the A3 receptor. What is going on?
When the A3 receptor gene was introduced into hamster cells, it was expressed and inserted itself in the membrane of the cell. Once in the membrane this receptor may interact with hamster proteins which inhibited its normal sensitivity to caffeine. In brief, I believe this 100 microM inhibitor dosage is an artefact of the culture system. In a human colon cancer cell, the 10 microM inhibitory dosage may be correct.
In the next essay, I will cite papers showing that caffeine alone can induce apoptosis, in a p53 depedent manner, in human cancer cells. The dosage is 50-100 microM.
I realize that caffeine makes some people uncomfortable. There is nothing that I can do about this. This simple molecule can directly and indirectly, through the activation of the immune response, kill cancer and leukemia cells. You cannot ask for more.
Remember, if you are drinking coffee, you MUST use a light roast. The dark roasts contain very little caffeine.
Stay tuned...
Grouppe Kurosawa, Medicine in the Public Interest
I like my coffee European strong, so I have the darkest roast and 1 heaped T of coffee grounds per cup, made in one of those little Italian aluminum octagonal espresso pots, on the stove.
I have no way of knowing how much caffeine I'm getting, nor how much I'd get from the lightest roast. So I'm thinking of switching to generic caffeine pills, 200 mg each.
Is synthetic caffeine bio-identical to phyto-caffeine?
Comments?
Posted by: satx2 | February 29, 2008 at 04:31 PM
Take the pills. You are not getting any caffeine from the coffee you use.
Posted by: Dr. Steve Martin | February 29, 2008 at 05:01 PM