As far as I can tell, caffeine metabolism occurs primarily via the CYP1A2 enzyme. I am curious as to whether mutations in the CYP1A2 gene are associated with caffeine intolerance. Some site that is not necessarily reputable suggested that caffeine intolerance is due to absence of the enzyme to metabolize caffeine. I am having difficulty finding evidence either supporting or contradicting this claim.

Does anyone know if there is evidence that suggests mutations in CYP1A2 (and therefore inability to properly metabolize caffeine) are associated with caffeine intolerance, or if there is another proposed mechanism for caffeine intolerance?

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    $\begingroup$ Yesterday I learned about this cool database linker site called biograph.be, where you can type in a gene and suspected "disease" or condition and it will generate a map showing how they've been associated in literature. Here's a start: biograph.be/concept/graph/C0006644/C1332826 $\endgroup$
    – yelx
    Commented Mar 16, 2013 at 3:19
  • $\begingroup$ Unfortunately, neither 'caffeine allergy' nor 'caffeine intolerance' are recognized search terms. But that is a cool site. Thanks for the link. $\endgroup$
    – blep
    Commented Mar 16, 2013 at 3:24
  • $\begingroup$ Yes, that links to the association between caffeine and CYP2A1 - but all of the papers that come up seem to be related to pharmacological inhibition of the enzyme, which I already know is important for caffeine metabolism...I'm interested in mutations in the gene. $\endgroup$
    – blep
    Commented Mar 16, 2013 at 3:28

1 Answer 1


I have found that caffeine is mostly metabolized over CYP1A2 (as we know), but also over CYP1A1, CYP2E1 and CYP3A4. The question is how much the individual can cope with this alternate pathways if he is a CYP1A2 poor metabolizer. [1]

Secondly I found in my pharmaceutics textbook that CYP2A1 activity determination is indicated due to undesirable side effects to caffeine and theophyllin.[2]

UPDATE: 19.03.2013 12:30 GMT+1

@dd3: To clarify the second statement: I used the approach that theophyllin and caffeine are similar xanthin derivates. Since theophyllin is used as therapeutic drug in respiratory diseases (COPD etc.), I thought that scientific interest would be greater. And yes CYP1A2 plays an important role in both theophyllin tolerance and intollerance.

I found some new sources:

At first a study with CYP1A2 knock-out mice, which shows that the elimination of theophyllin takes 4-times longer in CYP1A2(-/-)mice. And they also assume that the same behaviour is also applicable to caffeine. [3]

Also there are two clinical studies by Japanese and Turkish scientists. The Japanese conclude, that theophyllin should be used with care in CYP1A2 poor metabolizer (even in haplotype poor metabolizer), since theophyllin has a narrow therapeutic range.[4] But the Turkish scientist assume that according to their findings, theophyllin is also metabolized over alternative pathways such as CYP2A13, CYP1A1, CYP2E1, CYP2D6 and CYP3A4. And according to this the genetic status of CYP1A2 is not as important as expected. [5]

Conclusion: Assuming that theophyllin and caffeine are metabolized similarly, you can conclude that a mutation in CYP1A2 would lead to caffeine intolerance. In my experience people with caffeine intolerance describe severe nervousness after drinking a cup of coffee. Fatal cases I know were due to high consumption of energy drinks in children without or at least not known caffeine intolerance.


Further Reading:

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    $\begingroup$ Could you clarify your second statement? I'm not sure what you mean. Google translate of the second page seems to indicate that mutations of CYP1A2 are associated with both caffeine tolerance and intolerance -- is this correct? $\endgroup$
    – blep
    Commented Mar 19, 2013 at 1:30

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