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Huge energy today with Grapefruit and Ubiquinol (Coenzyme Q10). We'll see about tomorrow.

BeautifulDay

BeautifulDay

Senior Member
Messages
372
andyguitar said:
Great thread this,and some fantastic and very complex input from members. I have been looking at the enzyme that grapefruit inhibits and wonder if it is the inhibition of it that is having the theraputic effect. It's CYP3A4. If any of you want to have a look at what it does stick it in your search engine.
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Hi @andyguitar

That’s a similar question to what I’ve been asking myself. I don’t have a copy of the full study out of Japan (just the Abstract and articles interviewing the researchers), so it’s hard to know for sure. But let’s look at it together.

Grapefruit is complex because it contains multiple powerful items. I’m going to have to work it through in my head. Forgive me for backtracking. Also forgive me for using Wikipedia a lot in this post. When I’m new to a subject, I don’t have the basic knowledge to go straight to studies. I always need a few basic building blocks first.

Per Wikipedia:
“Grapefruit and grapefruit juice have been found to interact with numerous drugs and in many cases, to result in adverse direct and/or side effects (if dosage is not carefully adjusted.)[24]
This happens in two very different ways. In the first, the effect is from bergamottin, a natural furanocoumarin in both grapefruit flesh and peel that inhibits the CYP3A4 enzyme, (among others from the P450 enzyme family responsible for metabolizing 90% of drugs). The action of the CYP3A4 enzyme itself is to metabolize many medications.[25][26] If the drug's breakdown for removal is lessened, then the level of the drug in the blood may become too high or stay too long, leading to adverse effects.[26] On the other hand, some drugs must be broken down to become active, and inhibiting CYP3A4 may lead to reduced drug effects.
The other effect is that grapefruit can block the absorption of drugs in the intestine.[26] If the drug is not absorbed, then not enough of it is in the blood to have a therapeutic effect.[26] Each affected drug has either a specific increase of effect or decrease.”
https://en.wikipedia.org/wiki/Grapefruit

Per Wikipedia above, it’s the bergamottin that inhibits the CYP3A4.

Wikipedia further describes bergamottin as:
“In chemical terms, bergamottin and dihydroxybergamottin are linear furanocoumarins functionalized with side chains derived from geraniol. They are inhibitors of some isoforms of the cytochrome P450 enzyme, in particular CYP3A4.[2] This prevents oxidative metabolism of certain drugs by the enzyme, resulting in an elevated concentration of drug in the bloodstream.
Under normal circumstances, the grapefruit juice effect is considered to be a negative interaction, and patients are often warned not to consume grapefruit or its juice when taking medication. However, some current research is focused on the potential benefits of cytochrome P450 inhibition.[3] Bergamottin, dihydroxybergamottin, or synthetic analogs may be developed as drugs that are targeted to increase the oral bioavailability of other drugs. Drugs that may have limited use because they are metabolized by CYP3A4 may become viable medications when taken with a CYP3A4 inhibitor because the dose required to achieve a necessary concentration in the blood would be lowered.[4]
An example of the use of this effect in current medicines is the co-administration of ritonavir, a potent inhibitor of the CYP3A4 and CYP2D6 isoforms of cytochrome P450, with other antiretroviral drugs. Although ritonavir inhibits HIV replication in its own right its use in these treatment regimens is to enhance the bioavailability of other agents through inhibition of the enzymes that metabolize them.”
https://en.wikipedia.org/wiki/Bergamottin

Reading that I thought – oh maybe the drug ritonavir might be used instead of grapefruit, but it looks like it has many side effects, including:
“asthenia, malaise, diarrhea, nausea and vomiting, abdominal pain, dizziness, insomnia, sweating, taste abnormality, metabolic, hypercholesterolemia, hypertriglyceridemia, elevated transaminases, elevated CPK, and hyperglycemia.” It also appears to have bad interactions with many medications.
https://en.wikipedia.org/wiki/Ritonavir

Per an article on the Japanese study into grapefruit and CoQ10, “The juice appears to inhibit a protein in the membrane of cells called P-clycoprotein (P-gp), which thereby leads to an increased absorption of COQ10….”
https://www.nutraingredients.com/Article/2010/01/15/Grapefruit-juice-may-boost-CoQ10-uptake-Study#

The study's abstract states that: “It has been reported that efflux transport of CoQ10 is mediated by P-glycoprotein (P-gp) in Caco-2 cells. We tried to improve intestinal absorption of CoQ10 by modulating P-gp. Since grapefruit juice (GFJ) is reported to inhibit P-gp function, we investigated the effect of GFJ on the transport of CoQ10 by Caco-2 cells. In the presence of GFJ, the basal-to-apical transport of CoQ10 was decreased and the uptake of CoQ10 was increased. These findings suggest that the combined administration of CoQ10 and GFJ could enhance CoQ10 absorption.”
https://www.sciencedirect.com/science/article/pii/S030881460901245X

Ok, so now I have to look up what the word efflux means. Again to Wikipedia.
“Active efflux is a mechanism responsible for moving compounds, like neurotransmitters, toxic substances, and antibiotics, out of the cell; this is considered to be a vital part of xenobiotic metabolism. This mechanism is important in medicine as it can contribute to bacterial antibiotic resistance.
Efflux systems function via an energy-dependent mechanism (active transport) to pump out unwanted toxic substances through specific efflux pumps. Some efflux systems are drug-specific, whereas others may accommodate multiple drugs with small multidrug resistance (SMR)[1] transporters.[2]
https://en.wikipedia.org/wiki/Efflux_(microbiology)

So we know from the very top of this post that grapefruit inhibits the CYP3A4 enzyme. Does that then inhibit the P-gp function or does grapefruit directly inhibit the P-gp function in addition to CYP3A4? In fact what is the P-gp function? Yes, I have to talk to myself just like this to work things through my head. It’s how my brain works.

Per Wikipedia,
“P-glycoprotein 1 (permeability glycoprotein, abbreviated as P-gp or Pgp) also known as multidrug resistance protein 1 (MDR1) or ATP-binding cassette sub-family B member 1 (ABCB1) or cluster of differentiation 243 (CD243) is an important protein of the cell membrane that pumps many foreign substances out of cells. More formally, it is an ATP-dependent efflux pump with broad substrate specificity. It exists in animals, fungi and bacteria and likely evolved as a defense mechanism against harmful substances.
P-gp is extensively distributed and expressed in the intestinal epithelium where it pumps xenobiotics (such as toxins or drugs) back into the intestinal lumen, in liver cells where it pumps them into bile ducts, in the cells of the proximal tubule of the kidney where it pumps them into urinary filtrate (in the proximal tubule), and in the capillary endothelial cells composing the blood–brain barrier and blood-testis barrier, where it pumps them back into the capillaries.
P-gp is a glycoprotein that in humans is encoded by the ABCB1 gene.[4] P-gp is a well-characterized ABC-transporter (which transports a wide variety of substrates across extra- and intracellular membranes) of the MDR/TAP subfamily.[5] The normal excretion of xenobiotics back into the gut lumen by P-gp pharmacokinetically reduces the efficacy of some pharmaceutical drugs (which are said to be P-gp substrates). In addition, some cancer cells also express large amounts of P-gp, further amplifying that effect and rendering these cancers multidrug resistant. Many drugs inhibit P-gp, typically incidentally rather than as their main mechanism of action; some foods do as well. Any such substance can sometimes be called a P-gp inhibitor.
https://en.wikipedia.org/wiki/P-glycoprotein

On the same Wikipedia page, it states that: “In addition, some cancer cells also express large amounts of P-gp, further amplifying that effect and rendering these cancers multidrug resistant.”

I wonder if having an increased efflux transportation system (I’m using my new words), if that makes it better at clearing out things like cancer. I mean besides the effect on the cancer drugs. Just wondering out loud. So is slowing down that cleaning out system in order to upregulate the absorption of CoQ10 going to increase cancer. It’s another thing to research in studies. But if that’s the case, then why in the prior paragraph do some cancer cells express large amounts of P-gp? And in being low on ATP, and then increasing it with by supplementing with CoQ10, does that then make the whole body work better, therefore overcoming any cancer issues, with cancer decreasing health. OK, off track again.

The Wikipedia page also states that down regulation of P-gp has some negative things too.
“Decreased P-gp expression has been found in Alzheimer’s disease brains.[31]
Altered P-gp function has also been linked to inflammatory bowel diseases (IBD),[32] however, due to its ambivalent effects in intestinal inflammation many questions remain so far unanswered.[33] While decreased efflux activity may promote disease susceptibility and drug toxicity, increased efflux activity may confer resistance to therapeutic drugs in IBD.[33] Mice deficient in MDR1A develop chronic intestinal inflammation spontaneously, which appears to resemble human ulcerative colitis.[34]”

According to an article in journal Australian Prescriber, “P-glycoprotein has a very wide substrate spectrum similar to CYP3A4. ….. As many P-glycoprotein substrates are also substrates of CYP3A4 and because P-glycoprotein inhibitors are also inhibitors of CYP3A4, many drug-drug interactions are related to inhibition or induction of both P-glycoprotein and CYP3A4.”
https://www.nps.org.au/australian-p...rotein-and-its-role-in-drug-drug-interactions

I believe that’s the best answer I can give right now. P-gp and CYP3A4 are similar, but not necessarily the same thing. But then there is this.

There is an interesting study titled “Inhibitory effects of CYP3A4 substrates and their metabolites on P-glycoprotein-mediated transport”
“Abstract. It is generally known that the substrates and/or inhibitors of cytochrome P450 (CYP) 3A4 and P-glycoprotein (P-gp) overlap with each other. In intestinal epithelial cells, it is surmised that the metabolites coexist with their parent drug. However, most studies on P-gp did not take the effects of those metabolites into consideration. Therefore, in the present study, we investigated the inhibitory effects of five substrates of CYP3A4 (nifedipine, testosterone, midazolam, amiodarone, and azelastine) and their metabolites on the P-gp-mediated transcellular transport. The transcellular transports of [(3)H]daunorubicin or [(3)H]digoxin by monolayers of LLC-GA5-COL150 cells in which P-gp was overexpressed were measured in the presence or absence of the CYP3A4 substrates and their metabolites. Nifedipine, testosterone, midazolam, and their metabolites exhibited no effects on the P-gp-mediated transport of [(3)H]daunorubicin and [(3)H]digoxin. On the other hand, the transport of [(3)H]daunorubicin was strongly inhibited by amiodarone, desethylamiodarone, azelastine, and desmethylazelastine, with IC(50) values of 22.5, 15.4, 16.0 and 11.8 microM, respectively. The transport of [(3)H]digoxin was also strongly inhibited by these compounds, with IC(50) values of 45.6, 25.2, 30.0 and 41.8 microM, respectively. Another metabolite of azelastine, 6-hydroxyazelastine, exhibited no effects on these transports. It was suggested that the CYP3A4 metabolites of which their parent drug exhibited inhibition on the P-gp-mediated transport are possibly also inhibitors. It would be possible more complicated drug-drug interactions would be caused by the metabolites as well as their parent drugs in the liver and the intestine via the inhibition of CYP3A4 and P-gp."
https://www.ncbi.nlm.nih.gov/pubmed/11231118

In an article in Pharmacy Times, it states that “Many drugs that are CYP3A4 substrates, inhibitors, and inducers are also substrates, inhibitors, or inducers of the ABC transport protein known as P-glycoprotein. Many drug interactions, therefore, involve additive effects of both CYP3A4 and P-glycoprotein.”
http://www.pharmacytimes.com/publications/issue/2008/2008-09/2008-09-8687

I only have the abstract of the study from Japan. In that abstract, there is no mention of CYP3A4, but it does mention P-gp. We know that grapefruit inhibits the CYP3A4 enzyme. The study out of Japan shows that grapefruit also inhibits the P-gp allowing increased absorption of CoQ10. From all the above in this post, CYP3A4 and P-gp have many similar drug interactions and overlap. So it looks like the grapefruit is going to impact both CYP3A4 and P-gp, but the only study I know of shows that CoQ10 absorption is increased thru the inhibition of P-gp. I don't know of any that mention CYP3A4. However, due to so many studies showing the overlap, it’s likely to be both despite the lack of studies. How's that. :rolleyes:
 
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andyguitar

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Yes @BeautifulDay the effect of Grapefruit may well be down to its ability to increase CoQ 10 absorption and the effect on CYP3A4. I have also been looking at other drugs that have an effect on CYP3A4. What I am wondering is if Ritonavir, and some other anti virals were found to be effective in ME/CFS, it might have nothing to do with their anti viral effect and just be due to them blocking CYP3A4. Much more reading to do on this so it will be off to the library for me, to look in some of the books on herbal medicine.
 
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andyguitar

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Had a read of the Japanese study. Hmmm not sure that the effect they found is strong enough to bring about the level of improvement that @BeautifulDay has reported. So at the moment I am going to go for it being an increase in CoQ10 and something else. The P450 enzyme group is not something I have come across before. But having had a look at some of the PubMed papers it's something I see as worthy of investigation. Not just because there is a posibility that blocking the enzyme may be of thereputic value but also elevated levels of it may provide a diagnostic marker. BD do you think your level of improvement is in line with the findings of the Jap study?
 
BeautifulDay

BeautifulDay

Senior Member
Messages
372
andyguitar said:
Had a read of the Japanese study. Hmmm not sure that the effect they found is strong enough to bring about the level of improvement that @BeautifulDay has reported. So at the moment I am going to go for it being an increase in CoQ10 and something else. The P450 enzyme group is not something I have come across before. But having had a look at some of the PubMed papers it's something I see as worthy of investigation. Not just because there is a posibility that blocking the enzyme may be of thereputic value but also elevated levels of it may provide a diagnostic marker. BD do you think your level of improvement is in line with the findings of the Jap study?
Click to expand...

I'm not sure. It's so surprising to be able to do things that I haven't done in so long. Yet, it's still not normal compared with normal people. I'm thinking about experimenting with the level of grapefruit to 1/4 grapefruit in the morning and a 1/4 at lunch and see if it makes a difference.
 
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andyguitar

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Yes, spreading the dose out makes sense. If your level of activity has been quite low for a long time it will take months for your body to get back to normal, ie muscle strength,endurance ect. Many first hand accounts of how Noni Juice has helped those with CFS and lots of other health problems. Grapefruit has many useful properties but trying to work out what does what is a bit of a nightmare. There is a lot there! For instance CYP3A4 raises Estrogen levels in women who take the contraceptive pill or Hormone replacement therapy.
 
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BeautifulDay

BeautifulDay

Senior Member
Messages
372
pattismith said:
@BeautifulDay

you can below find the full article of the japanese study ;)
Click to expand...

Pretty much like us, the study authors are unsure of the impact of grapefruit on CYP3A4 and CoQ10 absorption, whereas the study does find the impact on P-gp. The only mention of CYP3A4 in the study is:
"Numerous reports have documented drug interactions with GFC (grapefruit juice) that occur via inhibition CYP3A4 (Dahan & Amidon, 2009). However, to date, there has been no report that CoQ10 is a substrate for CYP3A4."
 
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andyguitar

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So then when it comes to hard science we are a bit in the dark. But there is a pattern. You take grapefruit with CoQ10 and are much better than you have been for a long time, and the impovement is sustained. What's needed now is for others to give it a go and see what happens.
 
BeautifulDay

BeautifulDay

Senior Member
Messages
372
andyguitar said:
So then when it comes to hard science we are a bit in the dark. But there is a pattern. You take grapefruit with CoQ10 and are much better than you have been for a long time, and the impovement is sustained. What's needed now is for others to give it a go and see what happens.
Click to expand...

The big issue the scientists found was that while CoQ10 is hard to absorb, grapefruits impact on P-gp increases absorption significantly. The science is still out on if it impacts CYP3A4. So I wouldn't say we are in the dark. The 50% increase in absorption is from a study. But the depth, breadth, etc.... for these studies needs to increase. Yet why would a pharmaceutical company invest in such a study on grapefruit? They are more likely to invest in a study of a new med that includes a compound taken from the grapefruit.
 
BeautifulDay

BeautifulDay

Senior Member
Messages
372
Stretched said:
Aren’t pomegranate and grapefruit cautionary with some classes of medicines; and does anyone know which, or why so?
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Hi @Stretched

The below was on the first page of this thread. This thread contains a lot of information, so it definitely should be repeated. Thanks!

"First, a warning to those taking any medications, including statins. Please make sure you are allowed to eat grapefruit or drink grapefruit juice. There are many medications where the interaction if very negative with prescriptions. Here is an FDA article on drug interactions with grapefruit and why it occurs.
https://www.fda.gov/ForConsumers/ConsumerUpdates/ucm292276.htm
 
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andyguitar

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The reason the pharmacutical industry investigates grapefruit is to see what drugs it could interact with in a way which would be harmful. And to try to identify exactly what element in it causes the problem. There is probably much investigation regarding the medicinal properties of plants-including grapefruit- that is kept secret for commercial reasons. Watercress also inhibits an enzmye of the same family, P450 2E. What strikes me about Grapefruit, Noni, Pomegranate and Watercress is that they are all regarded in herbal medicine as being particularly useful. Lots on the net about Noni being useful for CFS. Going to have a look round, see what I can find.
 
Stretched

Stretched

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705
Location
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Lots on the net about Noni being useful for CFS. Going to have a look round, see what I can find. Big scam on Noni Juice in
Panama~10 year’s ago. See names MacMahon and Lennon. Some went to federal prison. Reported by Okke Orenstein.
 
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