19 replies to this topic

[greece]

There are many studies which confirm that pomegranate juice inhibits Cytochrome P450 3A4 (like grapefruit).
This does not sound good to me....
We don't know how pomegranate interacts with common medications. But for sure increases blood levels of many medications.
In addition a Cytochrome P450 inhibitor may lead to further problems to men with sensitive liver !!!

What is your opinion?

[fearfrost]

Well, Im not an expert, but I do have a story.

I just started taking pomegranate, resveratrol, and lecithin supplements about 3 weeks ago. During Christmas break, my aunt gave me a nasty cold. I rarely take medicine, but to help me sleep I took some tylenol nighttime cold pills. Holy crap! Usually they just make me a bit drowsy and feel a little better, but this time they knocked me out hard and gave me a weird medicine-head feeling. The next morning I could still feel the effects and for the remainder of the morning I was very spacy and disoriented.... or more like disconnected. That was 12 hours after I took the pills.

Nothing quantitative, and I am not sure if the pills I have been taking made this happen, but it very well could be.

[niner]

3A4 is one of the major p450s, and there are some drugs that are metabolized mostly by 3A4. Frequently a drug will be metabolized by more than one p450 (there are about 5 major p450s that are responsible for most oxidative metabolizm of xenobiotics, and a bunch more minor ones) If you are taking a compound for which 3A4 is the main or only metabolic enzyme, and IF pomegranate is a significant 3A4 inhibitor, then yes, you could have a problem. Does anyone know of a list of p450 inhibition/induction profiles for all the major supplements? It would be really good for such a thing to exist...

[ora101]

Well, Im not an expert, but I do have a story.

I just started taking pomegranate, resveratrol, and  lecithin supplements about 3 weeks ago.  During Christmas break, my aunt gave me a nasty cold.  I rarely take medicine, but to help me sleep I took some tylenol nighttime cold pills.  Holy crap!  Usually they just make me a bit drowsy and feel a little better, but this time they knocked me out hard and gave me a weird medicine-head feeling.  The next morning I could still feel the effects and for the remainder of the morning I was very spacy and disoriented.... or more like disconnected.  That was 12 hours after I took the pills. 

Nothing quantitative, and I am not sure if the pills I have been taking made this happen, but it very well could be.

Assuming the tylenol PM had benadryl in it, your ACh levels probably became temporarily fucked. AKA, the benadryl "hangover", a common result that many people report.

In a word, benadryl is shit. A Dr. told me it has been shown to reduce IQ scores if taken the night before a test.

BTW, which brand of pomegranate supplement did you take?

[fearfrost]

The active ingredients for Tylenol Cold Night are:
Acetaminophen 650 mg
Chlorpheniramine maleate 4 mg
Dextromethorphan HBr 20 mg
Phenylephrine HCl 10 mg

I dont think any of those are benadryl (aka: Diphenhydramine hydrochloride)

The pomegranate supplement I take is: Herbal Plus® Pomegranate by GNC

what are ACh levels? and do you think that is what happened looking at the ingredients now? Thanks.

Edited by fearfrost, 04 January 2007 - 03:03 AM.

[ora101]

Ah, my mistake then. I really have no idea then, but that appears to be a pretty potent combination of drugs in the Tylenol which could have any number of reactions with P450 and other supplements you are taking. Also I'd be wary of the quality of GNC branded products beyond basic generic substances (i.e. ascorbic acid, niacin, lecithin, etc..) .

ACh=

Acetylcholine (ACh) was first identified in 1914 by Henry Hallett Dale for its actions on heart tissue. It was confirmed as a neurotransmitter by Otto Loewi who initially gave it the name vagusstoff because it was released from the vagus nerve. Both received the 1936 Nobel Prize in Physiology or Medicine for their work.

Later work showed that when acetylcholine binds to acetylcholine receptors on skeletal muscle fibers, it opens voltage gated sodium channels in the membrane. Sodium ions then enter the muscle cell, stimulating muscle contraction. Acetylcholine, while inducing contraction of skeletal muscles, instead induces decreased contraction in cardiac muscle fibers. This distinction is attributed to differences in receptor structure between skeletal and cardiac fibers. Acetylcholine is also used in the brain, where it tends to cause excitatory actions. The glands that receive impulses from the parasympathetic part of the autonomic nervous system are also stimulated in the same way.

Acetylcholine is synthesized in certain neurons by the enzyme choline acetyltransferase from the compounds choline and acetyl-CoA. Organic mercurial compounds have a high affinity for sulfhydryl groups, which causes dysfunction of the enzyme choline acetyl transferase. This inhibition may lead to acetylcholine deficiency, and can have consequences on motor function.

Benadryl=Anticholinergic

An anticholinergic agent is a member of a class of pharmaceutical compounds which serve to reduce the effects mediated by acetylcholine in the central nervous system and peripheral nervous system.

Anticholinergics are typically reversible competitive inhibitors of one of the two types of acetylcholine receptors, and are classified according to the receptors that are affected: antimuscarinic agents operate on the muscarinic acetylcholine receptors, and antinicotinic agents operate on the nicotinic acetylcholine receptors. The majority of anticholinergics are antimuscarinics."

[niner]

I'm taking pomegranate extract daily, so I looked further into the p450 inhibition issue. It turns out that many fruit juices are p450 inhibitors, chiefly CYP3A. (CYP = CYtochrome P450) Pomegranate juice is also a 2C9 inhibitor (PMID: 17132763). The juices are 3A inhibitors in the following order: grapefruit > black mulberry > wild grape > pomegranate > black raspberry. (PMID: 16415112) Starfruit is also inhibitory, although I don't know where it fits in this scheme. Lime juice was seen to be an apparent 3A4 inhibitor in some subjects. (PMID: 12811362) Even red wine is a mild 3A4 inhibitor, and can lead to clinically relevant inhibition in some people. (PMID: 11452240)

The fruit juices all appear to act via a mechanism-based process. This means that they are covalently alterning the p450 enzyme rather than just taking up space in the active site while they are present in high concentration. As such, the inhibition continues until the enzyme is recycled. After grapefruit juice consumption, it may take from 3 (PMID: 12891222) to 7 (PMID: 11061578) days for the metabolism of certain drugs to return to normal.

Several studies looked at fresh versus processed or heat treated juices, and saw no differences. This suggests that the inhibition is due to a reasonably robust small molecule, rather than a proteolytic activity.

The juices appear to affect only the enteric p450s. The hepatic p450s seem to be left alone, from my reading. Apparently some people have more p450 activity in the gut (and less in the liver?) than others, so the juices hit them harder.

Are these inhibitions clinically relevant? Yes, it appears that they are. "When simvastatin was taken with grapefruit juice, the mean peak serum concentration (Cmax) and the mean area under the serum concentration-time curve [AUC(0-infinity)] of simvastatin were increased 12.0-fold (P < .001) and 13.5-fold (P < .001), respectively, compared with control." (PMID: 11061578) "48-year-old man with possible underlying myopathy was successfully treated with ezetimibe 10 mg/day and rosuvastatin 5 mg every other day for 17 months. Three weeks before presentation, he began drinking pomegranate juice (200 ml twice weekly). He presented urgently with thigh pain and an elevated serum creatine kinase level (138,030 U/L, normal < 200 U/L). In conclusion, because both grapefruit and pomegranate juice are known to inhibit intestinal cytochrome P450 3A4, this report suggests that pomegranate juice may increase the risk of rhabdomyolysis during rosuvastatin treatment, despite the fact that rosuvastatin is not known to be metabolized by hepatic P450 3A4." (PMID: 16923466) This paper was published shortly before the paper that showed that pomegranate juice was a 2C9 inhibitor, and sure enough, rosuvastatin is metabolized by 2C9.

Pomegranate juice harmful? Like everything else that we are running experiments on ourselves with, it should be treated as a drug. In combination with statins, high dose pomegranate is indeed dangerous. Grapefruit juice is worse. If you are using these juices, you should make sure that any other drugs you take are safe in the presence of a 3A4 or 2C9 inhibitor.

From my own experience, pomegranate (at least in the dose of extract I use, approximately 660 cc/day juice equivalent) is not a super strong 3A4 inhibitor. One of my chronic medications is a 3A4 substrate, and I have used it with clarithromycin, an antibiotic (biaxin) that is a powerful 3A4 inhibitor. With biaxin, I strongly feel the overdose of the other med in a few days. I've been using pomegranate for about 2 weeks, and just the other night noticed a slight tinge of OD. So it's there, but not very strong. But that's me, and that's a medicine with a pretty good therapeutic index. I will keep taking pomegranate because it does great things, but will titrate my other meds as needed.

By the way, (as if this post were not long enough...) my doctor, a pretty smart guy, happily prescribed a 3A4 substrate and a potent 3A4 inhibitor to me at the same time, and my pharmacist cheerfully dispensed them. In theory, that never should have happened- so much for the theory. Whenever you get a prescription medication, ask the pharmacist for a package insert. (the one for the pros, not the Readers Digest version that they print out for consumers) It will usually discuss the metabolism of the drug in detail, and you can figure out for yourself if you might have a problem or not.

Thanks for the heads up on this, greece.

[fearfrost]

Kinda a side note here:

"[resveratrol] inhibited recombinant cytochrome P450 CYP1B1 enzyme activity at 1 um"
Source: Relationship between Mechanism, Bioavailibility, and Preclinical Chemopreventive Efficacy of Resveratrol: A Conundrum
-Andreas J Gescher and William P Steward

So back to my story, the resveratrol could have also been causing the problem, not just pomegranate extract.

[niner]

Kinda a side note here:

"[resveratrol] inhibited recombinant cytochrome P450 CYP1B1 enzyme activity at 1 um"
Source: Relationship between Mechanism, Bioavailibility, and Preclinical Chemopreventive Efficacy of Resveratrol: A Conundrum
-Andreas J Gescher and William P Steward

So back to my story, the resveratrol could have also been causing the problem, not just pomegranate extract.

I dunno... 1b1 is kind of obscure. The classic antihistamines like chorpheniramine are metabolized primarily in the liver, with 2d6 being implicated in the metabolism of chlorpheniramine in humans (PMID: 11994058). There are some common drugs that are 2d6 inhibitors- were you taking anything else? Feeling spacey is a pretty common side effect of antihistamines; you may never really figure out why it hit you this time. Something you ate?

[fearfrost]

Niner, I agree. I will probably never figure it out. Plus I dont really understand this stuff all that well. Thanks for you input.

[Athanasios]

I would be worried about this if it were a similar situation as bioperine. Bioperine's inhibition of the P450s is non-specific in both intestinal and liver, whereas grapefruit is that specific one in the intestine only. With bioperine, it may increase your exposure to carcinogens. With grapefruit and other juices, this does not appear to be the case.

Carcinogenesis. 2004 Feb;25(2):203-9. Epub 2003 Oct 24.Click here to read  Links
    Grapefruit juice intake does not enhance but rather protects against aflatoxin B1-induced liver DNA damage through a reduction in hepatic CYP3A activity.

        * Miyata M,
        * Takano H,
        * Guo LQ,
        * Nagata K,
        * Yamazoe Y.

    Division of Drug Metabolism and Molecular Toxicology, Graduate School of Pharmaceutical Sciences, Tohoku University, Aramaki, Aoba-ku, Sendai 980-8578, Japan. miyata@mail.pharm.tohoku.ac.jp

    Influence of grapefruit juice intake on aflatoxin B1 (AFB1)-induced liver DNA damage was examined using a Comet assay in F344 rats given 5 mg/kg AFB1 by gavage. Rats allowed free access to grapefruit juice for 5 days prior to AFB1 administration resulted in clearly reduced DNA damage in liver, to 65% of the level in rats that did not receive grapefruit juice. Furthermore, rats treated with grapefruit juice extract (100 mg/kg per os) for 5 days prior to AFB1 treatment also reduced the DNA damage to 74% of the level in rats that did not receive grapefruit juice. No significant differences in the portal blood and liver concentrations of AFB1 were observed between grapefruit juice intake rats and the controls. In an Ames assay with AFB1 using Salmonella typhimurium TA98, lower numbers of revertant colonies were detected with hepatic microsomes prepared from rats administered grapefruit juice, compared with those from control rats. Microsomal testosterone 6beta-hydroxylation was also lower with rats given grapefruit juice than with control rats. Immunoblot analyses showed a significant decrease in hepatic CYP3A content, but not CYP1A and CYP2C content, in microsomes of grapefruit juice-treated rats than in non-treated rats. No significant difference in hepatic glutathione S-transferase (GST) activity and glutathione content was observed in the two groups. GSTA5 protein was not detected in hepatic cytosol of the two groups. In microsomal systems, grapefruit juice extract inhibited AFB1-induced mutagenesis in the presence of a microsomal activation system from livers of humans as well as rats. These results suggest that grapefruit juice intake suppresses AFB1-induced liver DNA damage through inactivation of the metabolic activation potency for AFB1 in rat liver.

    PMID: 14578159 [PubMed - indexed for MEDLINE]

Curr Drug Metab. 2006 Jan;7(1):67-81.Click here to read  Links
    Altered CYP expression and function in response to dietary factors: potential roles in disease pathogenesis.

        * Murray M.

    Pharmacogenomics and Drug Development Group, Faculty of Pharmacy, University of Sydney, NSW 2006, Australia. michaelm@pharm.usyd.edu.au

    Increasing evidence implicates dietary factors in the progression of diseases, including certain cancers, diabetes and obesity. Diet also regulates the expression and function of CYP genes, which impacts on drug elimination and may also significantly affect disease pathogenesis. Upregulation of CYPs 2E1 and 4A occurs after feeding of experimental diets that are high in fats or carbohydrates; these diets also promote hepatic lipid infiltration, which is a component of the metabolic syndrome that characterises obesity. Increased availability of lipid substrates for CYPs can enhance free radical production and exacerbate tissue injury. Similar processes may also occur in other models of experimental disease states that exhibit a component of altered nutrient utilization. Food-derived chemicals, including constituents of cruciferous vegetables and fruits, modulate CYP expression and the expression of genes that encode cytoprotective phase II enzymes. Certain dietary indoles and flavonoids activate CYP1A expression either by direct ligand interaction with the aryl hydrocarbon receptor (AhR) or by augmenting the interaction of the AhR with xenobiotic response elements in CYP1A1 and other target genes. Other dietary chemicals, including methylenedioxyphenyl (MDP) compounds and isothiocyanates also modulate CYP gene expression. Apart from altered CYP regulation, a number of dietary agents also inhibit CYP enzyme activity, leading to pharmacokinetic interactions with coadministered drugs. A well described example is that of grapefruit juice, which contains psoralens and possibly other chemicals, that inactivate intestinal CYP3A4. Decreased presystemic oxidation by this CYP increases the systemic bioavailability of drug substrates and the likelihood of drug toxicity. Dietary interactions may complicate drug therapy but inhibition of certain CYP reactions may also protect the individual against toxic metabolites and free radicals generated by CYPs. Chemicals in teas and cruciferous vegetables may also inhibit human CYP enzymes that have been implicated in the bioactivation of chemical carcinogens. Thus, food constituents modulate CYP expression and function by a range of mechanisms, with the potential for both deleterious and beneficial outcomes.

    PMID: 16454693 [PubMed - indexed for MEDLINE]

[health_nutty]

I would be worried about this if it were a similar situation as bioperine. Bioperine's inhibition of the P450s is non-specific in both intestinal and liver, whereas grapefruit is that specific one in the intestine only. With bioperine, it may increase your exposure to carcinogens. With grapefruit and other juices, this does not appear to be the case. 

Thanks for the useful info on both Pom and bioperine

[zoolander]

nice work Chris.

[spacetime]

How great of an issue is Cytochrome P450 inhibition if one is not taking prescription drugs? I take pom, grapefruit, grape seed, quercetin, bioperine+curcumin all of which inhibit enzymes to some extent. Should I be concerned with the decreased metabolization of potential carcingoens and other toxins? Would the benefit derived from supplementing these anti-oxs outweigh hte potential negs, like enzyme inhibition?

[niner]

P450s are there for xenobiotic metabolism. "Xenobiotic" means any small molecule you might injest that isn't part of your normal nutrients. Examples of things they might metabolize would be small organic molecules from plants, fungi, or even animals. These might be toxins or they may be benign, or they might even be beneficial. Also, they would typically be hydrophobic compounds with poor water solubility. Compounds that are already very soluble don't really need further oxidation from p450s in order to be excreted. Assuming that you are not running around eating random weird stuff (like poorly characterized herbal supplements...), drinking bongwater, licking toads, sniffing glue or taking statins for high cholesterol, you might not need a full complement of p450s. cnorwood19 pointed out that bioperine inhibits hepatic p450s, so that would concern me personally. Most of the fruits only inhibit the gut p450s, so you are still "covered" by the liver, although not as well as in your native state. I only take pomegranate, and consider that to be worth the tradeoff. Grapefruit is the strongest of the fruit inhibitors of gut p450s. I'm not sufficiently up on the benefits of grapefruit to say if it's worth it or not.

[health_nutty]

P450s are there for xenobiotic metabolism.  "Xenobiotic" means any small molecule you might injest that isn't part of your normal nutrients.  Examples of things they might metabolize would be small organic molecules from plants, fungi, or even animals.  These might be toxins or they may be benign, or they might even be beneficial.  Also, they would typically be hydrophobic compounds with poor water solubility.  Compounds that are already very soluble don't really need further oxidation from p450s in order to be excreted.  Assuming that you are not running around eating random weird stuff (like poorly characterized herbal supplements...), drinking bongwater, licking toads, sniffing glue or taking statins for high cholesterol, you might not need a full complement of p450s.  cnorwood19 pointed out that bioperine inhibits hepatic p450s, so that would concern me personally.  Most of the fruits only inhibit the gut p450s, so you are still "covered" by the liver, although not as well as in your native state.  I only take pomegranate, and consider that to be worth the tradeoff.  Grapefruit is the strongest of the fruit inhibitors of gut p450s.  I'm not sufficiently up on the benefits of grapefruit to say if it's worth it or not.

Nice explaination niner!

[syr_]

I wonder about resveratrol P450 inhibition, which seems stronger than pomegranate juice.

[Daniel Cooper]

I'm taking pomegranate extract daily, so I looked further into the p450 inhibition issue. It turns out that many fruit juices are p450 inhibitors, chiefly CYP3A. (CYP = CYtochrome P450) Pomegranate juice is also a 2C9 inhibitor (PMID: 17132763). The juices are 3A inhibitors in the following order: grapefruit > black mulberry > wild grape > pomegranate > black raspberry. (PMID: 16415112) Starfruit is also inhibitory, although I don't know where it fits in this scheme. Lime juice was seen to be an apparent 3A4 inhibitor in some subjects. (PMID: 12811362) Even red wine is a mild 3A4 inhibitor, and can lead to clinically relevant inhibition in some people. (PMID: 11452240)

The fruit juices all appear to act via a mechanism-based process. This means that they are covalently alterning the p450 enzyme rather than just taking up space in the active site while they are present in high concentration. As such, the inhibition continues until the enzyme is recycled. After grapefruit juice consumption, it may take from 3 (PMID: 12891222) to 7 (PMID: 11061578) days for the metabolism of certain drugs to return to normal.

Several studies looked at fresh versus processed or heat treated juices, and saw no differences. This suggests that the inhibition is due to a reasonably robust small molecule, rather than a proteolytic activity.

The juices appear to affect only the enteric p450s. The hepatic p450s seem to be left alone, from my reading. Apparently some people have more p450 activity in the gut (and less in the liver?) than others, so the juices hit them harder.

Are these inhibitions clinically relevant? Yes, it appears that they are. "When simvastatin was taken with grapefruit juice, the mean peak serum concentration (Cmax) and the mean area under the serum concentration-time curve [AUC(0-infinity)] of simvastatin were increased 12.0-fold (P < .001) and 13.5-fold (P < .001), respectively, compared with control." (PMID: 11061578) "48-year-old man with possible underlying myopathy was successfully treated with ezetimibe 10 mg/day and rosuvastatin 5 mg every other day for 17 months. Three weeks before presentation, he began drinking pomegranate juice (200 ml twice weekly). He presented urgently with thigh pain and an elevated serum creatine kinase level (138,030 U/L, normal < 200 U/L). In conclusion, because both grapefruit and pomegranate juice are known to inhibit intestinal cytochrome P450 3A4, this report suggests that pomegranate juice may increase the risk of rhabdomyolysis during rosuvastatin treatment, despite the fact that rosuvastatin is not known to be metabolized by hepatic P450 3A4." (PMID: 16923466) This paper was published shortly before the paper that showed that pomegranate juice was a 2C9 inhibitor, and sure enough, rosuvastatin is metabolized by 2C9.

Pomegranate juice harmful? Like everything else that we are running experiments on ourselves with, it should be treated as a drug. In combination with statins, high dose pomegranate is indeed dangerous. Grapefruit juice is worse. If you are using these juices, you should make sure that any other drugs you take are safe in the presence of a 3A4 or 2C9 inhibitor.

From my own experience, pomegranate (at least in the dose of extract I use, approximately 660 cc/day juice equivalent) is not a super strong 3A4 inhibitor. One of my chronic medications is a 3A4 substrate, and I have used it with clarithromycin, an antibiotic (biaxin) that is a powerful 3A4 inhibitor. With biaxin, I strongly feel the overdose of the other med in a few days. I've been using pomegranate for about 2 weeks, and just the other night noticed a slight tinge of OD. So it's there, but not very strong. But that's me, and that's a medicine with a pretty good therapeutic index. I will keep taking pomegranate because it does great things, but will titrate my other meds as needed.

By the way, (as if this post were not long enough...) my doctor, a pretty smart guy, happily prescribed a 3A4 substrate and a potent 3A4 inhibitor to me at the same time, and my pharmacist cheerfully dispensed them. In theory, that never should have happened- so much for the theory. Whenever you get a prescription medication, ask the pharmacist for a package insert. (the one for the pros, not the Readers Digest version that they print out for consumers) It will usually discuss the metabolism of the drug in detail, and you can figure out for yourself if you might have a problem or not.

Thanks for the heads up on this, greece.

 

Resurrecting this old thread.

 

So do we have a any more information on the use of statins while consuming pomegranate juice?

 

Could one titrate up their statin while consuming pomegranate juice until they achieved their target cholesterol goal?  Or is not just an issue of slower metabolism of the drug?

 

 

[joelcairo]

Probably measuring the blood serum concentration of the drug or its active metabolites would be the accurate way to do it. I'm sure that could theoretically done with statins but I don't know if there's any way you can practically get access to such a test.

 

The good news is that, according to this web page, not all statins are affected by this issue:

http://cholesterol.a...pefruitstat.htm

 

[Kalliste]

Is there any information of possible interactions between smoking cannabis and consuming large amounts of black pepper, pomegranate apples and so on?

Would the consumption of pepper inhibit the excretion of aerosol related gunk from the lungs?

I did a forum search but did not come up with anything.