Caffeine and CYP1A2 detox pathway
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Caffeine and CYP1A2 detox pathway
Everybody doesn’t appreciate the effect of coffee, whatever it may taste. Understand that one person might have appreciated one morning cup of coffee, in the past, and short afterwards no longer being able to drink coffee for the rest of the whole day due to a slow metabolism.Is caffeine bad for you?
The answer depends on whether you're a CYP1A2 ultra-rapid metabolizer or a slow metabolizer. Maybe you're one of those people who can have an after-dinner cappuccino and still fall asleep at bedtime. Or maybe you're the opposite. Any caffeine after noon keeps you wide awake.
The difference lies in your genes. The CYP1A2 gene determines how your body metabolizes the caffeine found in your favorite beverages—like tea, coffee, and soda—and how it makes you feel.
Most people metabolize half of the xanthine from coffee in 4 hours, but for others no more coffee after breakfast at 8 a.m.Positive effects of caffeine on the metabolism
There’re well-known positive effects when drinking coffee (adrenergic or antioxidant effects). But not everyone will take advantage of them. Understand that – e.g. caffeine is a dopamine agonist and is expected to reduce prolactin, as dopamine agonists do (1) – another aspect might outweigh either advantage. It's probably not a surprise for most of the readers that caffeine is an adenosine receptor antagonist as shown by the table (2), but caffeine has other “nervous targets”, as 5-HT1 / 5-HT2 or GABA. By people with already low GABA and a tendency to have high level of adrenaline (up and down reactions), caffeine could push their GABA too low and adrenaline too high. The ground makes the difference.
Expressed differently, it would be worthwhile to stop coffee for a couple of days when you feel anxious or have stomach cramps. Mind taking a high level of B6 PLP too for several days (inducing a GABA withdrawal syndrome).What is caffeine—and how does it affect the body?
Caffeine is a bitter substance that’s found naturally in more than 60 different plants, including coffee beans, tea leaves, peppermint tea and kola nuts. Kola nuts are used to make soda.
Caffeine acts as a natural stimulant, and for this reason, the FDA lists it as both a food and a drug. Caffeine targets the central nervous system and makes you feel more awake, energized, and alert, as you know. It’s often described as a cognitive and physical performance enhancer.
But everyone seems to react differently to caffeine. Some people get jittery and anxious from a few sips of coffee, while others can drink cup after cup without blinking an eye.
Recently, researchers discovered these variations in caffeine tolerance can be traced back to genetic differences, which brings us to the CYP1A2 gene.What is CYP1A2, aka the caffeine gene?
The caffeine you ingest passes through the stomach and small intestine, entering the bloodstream in a little as 15 minutes. Your caffeine levels peak about 30 to 60 minutes after consumption and then start to decrease gradually.
The speed of this decline depends on your CYP1A2 gene, which controls an enzyme (also called CYP1A2) that is in charge of breaking down caffeine. (3)
You have two copies of the CYP1A2 gene—one inherited from each of your biological parents. And each copy can be either a “fast” or “slow” version of the gene.
If you have two fast versions, you’re considered a fast caffeine metabolizer. “These are the people that can have an espresso and go right to sleep," says Tiffany Lester, MD.
In contrast, if you have one or two versions of the slow version of CYP1A2, you’re labeled a slow caffeine metabolizer. This means you clear caffeine from your system about four times slower than your quick-metabolizing counterparts, says Dr. Lester.Cyp450
Most caffeine is metabolized in the liver by the cytochromes P450 (Cyp450) and predominantly by the CYP1A2 isozymes (95%). The P450s are heme based mono-oxygenases involved in the detoxification of xenobiotics and hence are the key drug metabolizing enzymes in the liver.
The biodegradation of caffeine gives paraxanthine, theobromine and theophylline products. Caffeine has a non-linear effect on thyroid. When taken in moderate amounts (9.97–264.97 mg/d), caffeine demonstrated a positive correlation with serum TSH levels in patients with metabolic disorders. (4)Other genes related to caffeine sensitivity
While CYP1A2 is the primary gene involved in caffeine metabolism, research suggests that other genes may also play a role.
ADORA2A is associated with caffeine sensitivity and its effects on anxiety and sleep disturbance. So even if you are a fast metabolizer, looking at ADORA2A can also help identify a problem with caffeine metabolism. (5)Pharmacokinetic interactions due to inhibition of drug metabolism
Some molecule could partly exhaust the capacity of the liver enzymes to detox residues after assimilation of some drugs (aspirin, quinolone, or phytonutrients like curcumin or polyphenols). Certain selective serotonin reuptake inhibitors, anti-psychotics, anti-arrhythmics, bronchodilators, etc. Since these drugs are metabolized by, or bind to, the same CYP enzyme, they have a high potential for pharmacokinetic interactions due to inhibition of drug metabolism. The detox pathway is slower; there is accumulation of drugs … (6)If you’re a slow metabolizer, should you avoid caffeine?
Slow metabolizers shouldn’t drink more than four cups of coffee per day, published the Journal of the American Medical Association in the mid-2000s, or they’ll have an increased risk for nonfatal heart attack.Estrogen dominance
Research suggests that, for healthy adults, a healthy caffeine intake can include up to 400 milligrams (mg) a day. (7) If you’re consuming more than that, you may wish to cut your caffeine intake, especially if you’re a slow caffeine metabolizer or are experiencing unpleasant side effects.
You may also be a fast caffeine metabolizer and still have negative reactions to moderate or even low amounts of caffeine. This could indicate an underlying health concern, such as estrogen dominance.
Estrogen and caffeine are both broken down in the liver by the CYP1A2 enzyme. ( 8 ) “Women that have estrogen dominance often do not have an abundance of this enzyme and therefore should not consume much caffeine as they will also have a hard time detoxing it,” explained Dr. Lester.
The good news is that once you balance your hormones with the help of a doctor, you’ll likely be able to tolerate caffeine again.
Additionally some people should not drink caffeine or should limit their intake because of underlying conditions or because of medication interactions. Check with your doctor to see if your medicine / drug impacts the same detox pathway CYP450 (here CYP1A2) as coffee or tea.How to reduce caffeine intake and avoid caffeine withdrawal symptoms
If you’ve decided to pull back on your caffeine intake for any reason, the first step is to figure out how much caffeine you’re actually consuming.
Not every beverage contains the same amount of caffeine. Here are a few examples. (9)
• 8 ounces of coffee (226 ml) : 95 to 200 milligrams
• 8 ounces of green tea: 14 to 60 milligrams
• 12 ounces of cola (a can 330 ml): 35 to 45 milligrams
• 8 ounces of an energy drink: 60 to 250 milligrams
“Each of these beverages has different amounts of caffeine with tea being the lowest. So, for example, someone with anxiety may not be able to tolerate an espresso but can happily drink a matcha latte,” Dr. Lester says.
Caffeine can also be hiding in places you might not expect. Kombucha and chocolate are two hidden sources of caffeine that you might not be taking into account, on top of the roof.
When you’re cutting back on caffeine, Dr. Lester recommends going slowly, or you might experience caffeine withdrawal symptoms like headaches, irritability, and fatigue.
“A general rule is to go by halves. Cut down gradually by halving your intake every three days until you’re completely off any caffeine source,” she said.
Comment (LucH): The effects of caffeine will largely depend on the health of your liver, how you metabolize, and how you manage “emotional events” (mood change with borderline or fluctuated hormone levels). -
Sources and References
0. Article inspired by Parshleyhealth.com
https://www.parsleyhealth.com/blog/cyp1a2-effects-of-caffeine-on-the-body/- Caffeine Effect on Various "receptors": Caffeine is an adenosine receptor antagonist.
Adenosine receptors have been implicated in several diverse physiological and pathophysiological roles in the body, including arousal, locomotion, regulation of cardiac contractility, vascular tone, adipocyte fat content, leukocyte activity, and diuresis. - http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3437321/
- CYP1A2 gene is in charge of breaking down caffeine
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4462044/ - Caffeine demonstrated a positive correlation with serum TSH levels in patients with metabolic disorders.
DOI https://doi.org/10.1186/s12937-023-00866-5 - ADORA2A gene is associated with caffeine sensitivity and its effects on anxiety and sleep disturbance.
https://pmc.ncbi.nlm.nih.gov/articles/PMC6947650/ - Interaction of caffeine with other molecules / drugs.
https://link.springer.com/article/10.2165/00003088-200039020-00004 - A healthy caffeine intake can include up to 400 milligrams (mg) a day.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6266969/ - Estrogen and caffeine are both broken down in the liver by the CYP1A2 enzyme.
https://pubmed.ncbi.nlm.nih.gov/16112414/ - amount of caffeine in some beverages
https://medlineplus.gov/caffeine.html
- Caffeine Effect on Various "receptors": Caffeine is an adenosine receptor antagonist.
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Interesting effects
*) Many of the pharma antiviral drugs used caffeine as adjuvant.
Caffeine Is a Strong Antibacterial Agent
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3125025
"...Caffeine and aminophylline had the ability to inhibit many strains of pathogenic bacteria."
http://www.ncbi.nlm.nih.gov/pubmed/8700184
"...Three purine nucleoside analogues, penciclovir (PCV), acyclovir (ACV) and ganciclovir...”
*) Caffeine Lowers Parathyroid Hormone (PTH)
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4207951/
PTH increases when calcium intake and blood levels fall. Its role is to get more calcium in the blood. PTH does this by increasing calcium absorption from the intestine by increasing conversion of vitamin D3 into the "active" vitamin D called calcitriol. However, PTH also increases prolactin so the net effect can be quite detrimental to the bone. If a person gets PTH as a drug and does not also increase calcium intake then it will shed their bones by elevating prolactin.
Conclusion:
A physiological high dose of caffeine inhibits PTH secretion in human parathyroid cells, possibly due to a decrease of the intracellular level of cAMP. The observation demonstrates a functional link between caffeine and parathyroid cell function.
*) Caffeine is a dopamine agonist and is expected to reduce prolactin, as dopamine agonists do.
https://raypeatforum.com/community/threads/caffeine-lowers-prolactin.2818/
As a follow up on my previous post on caffeine being a dopamine agonist, it follows naturally that it is expected to reduce prolactin (as dopamine agonists do):
http://onlinelibrary.wiley.com/doi/10.1002/hup.470040106/abstract
The study on life extension said 200mg every 4-6 hours. Other studies used different amounts for different purposes. For me (Haidut), 200mg every couple of hours works just fine without bringing in a stress reaction.
Note: The other studies are showing increased prolactin from 500mg caffeine per day but lower prolactin from 1,000mg+ per day.
*) Coffee is anti-inflammatory and good for diabetes (DT2 & DT3)
https://doi.org/10.1093/ajcn/nqy295
Results
Compared with nondrinkers, participants who drank ≥4 cups of total coffee/d had lower concentrations of C-peptide (−8.7%), IGFBP-3 (−2.2%), estrone (−6.4%), total estradiol (−5.7%), free estradiol (−8.1%), leptin (−6.4%), CRP (−16.6%), IL-6 (−8.1%), and sTNFR-2 (−5.8%) and higher concentrations of SHBG (5.0%), total testosterone (7.3% in women and 5.3% in men), total adiponectin (9.3%), and HMW adiponectin (17.2%). The results were largely similar for caffeinated and decaffeinated coffee.
Conclusion
Our data indicate that coffee consumption is associated with favorable profiles of numerous biomarkers in key metabolic and inflammatory pathways.
Comment: While it is known to be a factor in hypertension, recent studies show that, within reasonable limits, coffee actually has a hypotensive effect! A beneficial effect is seen with just two cups a day (between 2 and 4 cups).
