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Grapefruit Juice-A New Perspective
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Grapefruit Juice-A New Perspective

Cowriter and Merrybe and others on this board have warned about grapefruit juice's inhibition of cytochrome P450, which metabolizes drugs. While the inhibition of cytochrome P450 and its isoforms P2E1 and P3A4 is advantageous to protect your mitochondria from the damage caused by the hep c virus and to inhibit the virus from replicating, it can also inhibit your body's ability to metabolize some of the drugs you may be taking, exposing you to the possibility of overdose.

Medical researchers have just completed a new study involving grapefruit and very costly chemotherapy drugs, exploring grapefruit juices potential to amplify the effects of the drug. In a small, early clinical trial, researchers at the University of Chicago Medical Center have found that combining eight ounces of grapefruit juice with the drug rapamycin can increase drug levels, allowing lower doses of the drug to be given. They also showed that the combination can be effective in treating various types of cancer.

For two decades, pharmacists have pasted DO-NOT-TAKE-WITH-GRAPEFRUIT-JUICE stickers on various pill bottles because it can interfere with the enzymes that break down and eliminate certain drugs. This interference makes the drugs more potent. In data presented at the AACR 100th Annual Meeting 2009, the Chicago researchers examine ways to exploit this fruit’s medication-altering properties.

“Grapefruit juice can increase blood levels of certain drugs three to five times,” said study director Ezra Cohen, MD, a cancer specialist at the University of Chicago Medical Center. “This has always been considered a hazard. We wanted to see if, and how much, it could amplify the availability, and perhaps the efficacy of rapamycin, a drug with promise for cancer treatment.”

This study showed that substances known a furanocoumarins, plentiful in some forms of grapefruit juice, can decrease the breakdown of rapamycin. This makes the drug reach higher levels in the bloodstream, two to four times the levels seen without a juice boost, and thus increases the amount of the drug that reaches its targets.

“That means more of the drug hits the target, so we need less of the drug,” said Cohen.

Many of the newer cancer medications, precisely focused on specific targets, are now taken as pills rather than intravenously. Some of these drugs, including rapamycin, can cost thousands of dollars a month. Hence, “this is an opportunity for real savings,” Cohen said. “A daily glass of juice could lower the cost by 50 percent.”

I know that in some cases hep c patients on INF want to increase their dosages. Use of grapefruit juice may accomplish that. However, it would also disrupt the balance of many of the other drugs they may be taking. It certainly SHOULD NOT be done without asking your doctors advice.

Just food for thought.

Mike H
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Avatar_m_tn
Just to complete the info on the subject here is original post by merrybe quoting the post by cowriter. Excellent synopsis, in my opinion.

Cytochrome P450  is a group of enzymes. "Cyto", means cell.  "Chrome" means color.   Cytochromes are colored with iron.  Cytochrome P450  is located on the inner membrane of the mitochondria of liver cells (the mitochondria is the powerplant of the cell...it stores oxygen to power the cell).  CYP450, is a target of the hepatitis C virus.  The virus gets help from CYP450.

Why does HCV target the mitochondria?  Because the mitochondria is the location of the interferon response mechanism. By damaging the mitochondria, the Hep C virus stops the interferon response.

So the CYP450 group of enzymes are implicated with liver destruction by Hepatitis C.   So it is possible that inhibiting CYP450, might give you more time to wait for a cure, might help slow down or reverse liver damage, and it may help other drugs clear the virus.  

CYP450 has other family members called isoforms.......

CYP2E1  - Causes mitochondrial damage and oxidative stress on the liver cell.  This is liver enzymes worst enemy.  Alcohol is a CYP2E1 substrate. Even in people who don't drink, CYP2E1 is implicated in non-alcoholic steatohepatitis (NASH)...fatty liver.  What inhibits CYP2E1?  Antabuse....the drug that helps you stop drinking alcohol by making you violently ill if you do drink.  The way it makes you sick is by inhibiting alcohol's metabolizer.  Whenever you inhibit a metabolizer, you raise the level of that drug in your bloodstream and liver....and it makes you sick.

CYP3A4   - Allows HCV to move from cell to cell.  Cell migration is one of the ways in which HCV keeps itself alive and multiplying.  It has to keep moving to new cells.  So inhibiting CYP3A4 will lower your viral load.

A recent study showed that grapefruit juice lowered viral load, because there's a bioflavanoid in grapefruit juice that inhibits CYP3A4.  

HOWEVER, the problem with inhibiting CYP450 enzymes is that many prescription drugs are metabolized by these enzymes..... and by inhibiting them, that can raise the level of the drug in your blood and it can cause an overdose.  (taking Tylenol and alcohol together can cause the level of Tylenol to be toxic.  That's why we always tell people that Tylenol by itself is not really a problem but never to take it with alcohol).

So for example, if you take a blood pressure medication that is metabolized by CYP3A4, inhibiting this enzyme with grapefruit juice may  raise the levels of the blood pressure med in your blood and IN YOUR LIVER....and it can cause an overdose (and your blood pressure to go down too low).

So if you want to lower your viral load by drinking grapefruit juice, you'll need to make sure that you're not taking any meds that are metabolized by CYP450.

(WARNING: Do not drink grapefruit juice during HCV treatment since it can cause oxidative stress and impact treatment success.  Also, be aware that the effect from a small amount of grapefruit juice can last all day).


Another enzyme, CYP1A2, is also implicated in liver damage (and tobacco related cancer)....and SMOKING INCREASES THE ACTIVITY OF THIS ENZYME THREEFOLD!!!!!  You know what else induces this enzyme?  Caffeine.....and Marijuana.....and exposure to polycyclic aromatic hydrocarbons, such as those found in charbroiled foods.:

It's all very complicated.....and some people are more sensitive than others ......and this info is very new.

You also have to be careful using supplements.....St. John's Wort, an over-the-counter anti-depressant, targets CytochromeP450....and interferon (and PI's) inhibits CYP450.  So basically, St John's Wort interferes with the interferon.


Something else that's important.....

HYPERINSULINEMIA  INCREASES CYP1A and CYP2E1  (fasting also induces CYP2E1).

Interferon is a CYP450 1A2 INHIBITOR....a WEAK inhibitor.  And insulin is a CYP450 1A2 INDUCER.  That's how I found out that it was the insulin that made interferon ineffective.  I had been looking for the causal connection between insulin resistance and interferon resistance......and it turned out to be insulin.  Hyperinsulinemia caused by insulin resistance.

(Hey....did you notice how well I stuck insulin resistance in the conversation?  I'm a master at it.....LOL)

Co
P.S,  Sorry.....I wrote you a book....LOL


And just in case you post this somewhere and they ask you for sources....

"CYP1A2 can be induced by exposure to polycyclic aromatic hydrocarbons, such as those found in charbroiled foods and cigarette smoke. This is the only CYP450 isoform affected by tobacco. Cigarette smoking can result in an increase of as much as threefold in CYP1A2 activity."

http://www.aafp.org/afp/980101ap/cupp.html


Hyperinsulinemia causes a preferential increase in hepatic P450 1A2 activity.
"administration of insulin ........also enhances P450 1A2 activity, presumably as a result of hyperinsulinemia."

http://www.ncbi.nlm.nih.gov/pubmed/1562279?dopt=Abstract


Star fruit is a better inhibitor of CYP3A than grapefruit juice.... POTENT INHIBITION BY STAR FRUIT OF HUMAN CYTOCHROME P450 3A (CYP3A) ACTIVITY

http://dmd.aspetjournals.org/cgi/content/abstract/32/6/581?ijkey=3142833449ed0472aa65ca659aaecdd53316e051&keytype2=tf_ipsecsha


Inhibitory effect of fruit juices on CYP3A activity.
"The inhibitory potential of human CYP3A was in the order: grapefruit > black mulberry > wild grape >pomegranate > black raspberry."

http://dmd.aspetjournals.org/cgi/content/abstract/34/4/521?ijkey=8fc3bc688dccea368d29077e08e6a92230856feb&keytype2=tf_ipsecsha


Effects of different spices (ginger) on CYP3A4

http://dmd.aspetjournals.org/cgi/content/abstract/36/7/1283

thanks again to CO
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Avatar_m_tn
Mike H wrote;

"I know that in some cases hep c patients on INF want to increase their dosages. Use of grapefruit juice may accomplish that. However, it would also disrupt the balance of many of the other drugs they may be taking. It certainly SHOULD NOT be done without asking your doctors advice.
------------------------------------------------------------

Mike thanks for the interesting post.  While it may be true that grapefruit juice may help triple the punch of certain cancer drugs it MAY NOT relate having the same effect on interferon.  
It is just my casual observation but most doctors when consulted about things which may or may not work will tell the patient to steer clear of the idea/ drug/ compound/ treatment until it is established in trials by the FDA.

I have heard that grapefruit juice does cause oxidative stress and therefore could either impact on fibrosis/ disease progression or TX response rates in spite of possibly having some antiviral effects on HCV.  More will be known in the future.

The principle you describe is also being used with the second generation PI from Shering-Plough which follows boceprevir.  I believe one or two trial arms are being used with ritonovoir (sorry, not going to check spelling or which HIV drug it is but it works the same way- keeps PI levels up allowing a lower dose or a longer half life).

Interesting idea, it may have some promise.  I have a feeling that the pharms are going to go all out on antivirals.  There is a question as to whether decent trials will be performed with grapefruit juice since the proof could impact on people taking less drugs.   We wouldn't want that now, would we?  ; )

With the pending approval of PI's we should see the success rate for geno 1's go to 75%, maybe 80%.  Then Stat-C trials get underway we may see further improved response rates.  Vertex could start their own Stat-C trials this year; probably a 4 week trial.  If the pattern were to follow the early TVR testing we could also hear of results of such a trial soon thereafter.  I have a hope that the response rates of those trials will end up further nixing the desire to spend money developing alternative type treatments.  It's a good news/bad news deal.  

In time the treatment could become much shorter and increasingly less like chemotherapy.  I'm sure that many will keep investigating for more natural means of staying healthy while waiting for such treatments.  It would be great if the impact of the disease could be minimized.

best,
Willy
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751342_tn?1297434382
I always wondered why I was never told by the study not to eat grapefruit or drink the juice if it was so bad. BTW, I just came off one of those Schering Plough studies that included Ritonavir. Should be posting a 4 week PCR in a few days. Thanks for an interesting post, Mike.
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Avatar_m_tn
Willy wrote,

"Interesting idea, it may have some promise.  I have a feeling that the pharms are going to go all out on antivirals.  There is a question as to whether decent trials will be performed with grapefruit juice since the proof could impact on people taking less drugs.   We wouldn't want that now, would we?  ; )
____________________________________

Your comment reminds me of the case of insulin potentiated chemotherapy (IPT). Because tumor cells have a natural nutrient hoarding mechanism, scientists have found that pretreatment with insulin "...has been shown to increase the cytotoxic effect of methotrexate in MCF-7 human breast cancer cells (HBCC), in vitro, by a factor of up to ten thousand. (Alabaster O., Vonderharr B.K., Shafie S.M. Metabolic modification by insulin enhances methotrexate cytoxicity in MCF-7 human breast cancer cells. Eur J Cancer Clin Oncol 1981; 17:1223-1228.) It has similar effects for other chemo drugs, allowing doctors to use a tenth of the drug with a greatly increased specificity for tumor cell absorption of the drugs, and much decreased side effects on healthy cells.

Well established science, but still only about ten doctors in the US are trained in IPT and health insurance covers none of it. Decreased dose with higher tumor cell specificity? Who would want that?

MIke H
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Avatar_m_tn
Annie,

good luck on your pcr, btw. Got my fingers crossed for you!

Mike H
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