Caffeine helps one, the other harms – why?

Before you unleash a storm in the comments, it’s worth remembering that caffeine is no exception to the rule. When prescribing medication, the suppression or induction of cytochrome P450 enzymes is taken into account (interactions between drugs affecting, for example, individual CYP families), liver and / or kidney status (depending on how it is metabolized and excreted), age, profile hormonal, co-existing diseases. For example, the substrates CYP3A4 and CYP3A5 are, for example, anabolic-androgenic steroids and hormones (eg testosterone, progesterone, estradiol, hydrocortisone) or antifogesterone agents such as mifepristone (the infamous RU-486), and even cocaine. 


Here you can find supplements with caffeine – CLICK 



And that means that when using the above-mentioned preparations should be well thought through administration of strong CYP3A4 / 3A5 inhibitors (eg clarithromycin, telithromycin – antibiotics, indinavir, ritonavir, saquinavir – medicines used in therapy eg HIV, antifungals itraconazole, ketoconazole, nefazodone – antidepressant; suboxone – a strong drug used in addiction therapy opioids). Why? Because the distribution of the above will slow down considerably. medicines, their concentration in the blood will increase. For example, 250 ml of grapefruit juice (median CYP3A4 / 5 inhibitor potency) given with 5 mg diazepam increased diazepam concentration 1.5 times, and the time to reach maximum drug concentration increased from 1.5 h to over 2 h!

Fast and slow caffeine metabolism 

As it turned out in the research, it is not the caffeine supply that counts, but also the genetic profile we have. People with rapid caffeine metabolism (specific polymorphism of the cytochrome 450 1A2 gene) are much less responsive to caffeine in terms of improving abstract thinking. 3 Most likely, high coffee intake is important, but only for some CYP1A2 genetic variants (eg -163C> A). It has been determined that the -163C> A variant is a slow metabolizer of caffeine, whereas -163 A> C is fast. For rapidly metabolizing, caffeine intake was not important for improving abstract thinking. Only those who were slow metabolizing caffeine intake were correlated with the onset of myocardial infarction (not fatal). In other studies, CYP1A2 * 1A variants were identified as rapid and CYP1A2 * 1F as free. 

Individuals who metabolize caffeine consuming 4 cups of coffee per day (or more) have been exposed to a 64% higher risk of having a heart attack. Meanwhile, people who rapidly metabolize caffeine even when consuming 4 cups of coffee a day (or more) were exposed to almost identical risk as when consuming 1 or fewer cups of coffee a day. Excessive consumption of caffeine is also associated with the occurrence of resistant hypertension (associated with the occurrence of strokes, heart and kidney disease).

Subsequent studies by Rogerio Nogueira Soares et al. 10 showed that caffeine has a completely different effect on blood pressure depending on the genotype correlated with CYP1A2. 

37 people aged 19-50 were divided according to the genotype 

Caffeine was given at a dose of 6 mg per kilogram of body weight and after 1 h the blood pressure was measured. 



Caffeine metabolism and developmental defects of children 

Caffeine metabolism


The main metabolite of caffeine, paraxanthin 

One of the paraxanthin metabolites is coupled via NAT2. And this is the quintessence of the problem. The term neural tube defects includes all inborn malformations that are associated with abnormal neural tube closure during the critical embryogenesis period, i.e. the fourth week of embryo development, with defects occurring anywhere along the forming spinal cord.

Many studies indicate that excess caffeine can be harmful to the developing fetus. But the matter is not so simple. Although caffeine is metabolized by the cytochrome P450 (CYP1A2) enzymes in the first phase (Campbelli et al., 1987), the second phase (coupling) is mediated by N-acetyltransferase  (NAT2). (Cascorbi et al., 1995). NAT2 occurs mainly in hepatocytes and, moreover, in cells of the reticuloendothelial system of the spleen, lungs and intestines.


Depending on the rate of metabolism of INH (and then other model medicines), two phenotypically different groups were distinguished in the human population 


In fast acetylators, the half-life of INH is 3-5 times shorter (45-80 min and 140-200 min.), Respectively, and 10 times less of the drug is excreted unchanged by the kidneys (respectively 3% and 30%)


The presence of neural tube defects is strongly associated with free acetylation through NAT2 in the child (twice the risk). The risk is also higher by 49% if the mother has a rapid metabolism of CYP1A2 (oxidation). Women who have a fast CYP1A2 metabolism (oxidation), and free acetylation of NAT2 have a much higher risk for the appearance of similar malformations (especially if the child quickly oxidizes xenobiotics).  



Everyone tolerates caffeine in a different way, and processes that take place with the participation of cytochrome P450 enzymes are even more important for health. Because of possible complications, pregnant women should avoid caffeine, especially that in recent years there have been many well-documented research in this field. Caffeine metabolism significantly accelerates smoking (induces two demethylation processes), which is why these people may be less sensitive to certain dietary supplements.