Okay, listen up, MGUSers and SMMers!

This morning a blog reader (super duper thanks!!!) sent me the link to a paper that will be presented at the upcoming ASH (=American Society of Hematology) annual meeting. See: http://tinyurl.com/ykye8pf

Well, this was a bit of a shocker (in a very good sense!) that made me drop everything I was doing and write this post…

In a nutshell, a Japanese MGUS patient (IgA-kappa) began taking something called hesperetin-7-glucoside, a more bioavailable form of hesperetin, which is a flavanone found in grapefruit and oranges (citrus fruit in general). And the patient’s M-protein decreased from 2,080 to 878 mg/dL over a three-year period. Her/his hematologists took notice, good for them!, and decided to test this compound on MM cells.

They found that Hesperetin showed inhibitory effects in a dose-dependent manner on the growth of 4 myeloma cell lines and freshly isolated myeloma cells. And hesperetin also turns out to be a proteasome inhibitor, just like curcumin and bortezomib (=Velcade). In the experiments, hesperetin annihilated the myeloma cells. Based on these results, an open-label, pilot clinical trial to test the efficacy of hespertin recently began for asymptomatic myeloma patients. Well, please go have a look at the abstract, which isn’t too difficult to read.

Now, this topic definitely deserves more attention, but today I have a bunch of errands to run, so I must put it on hold…like everything else, for that matter!

Oh heck, just quickly…let’s see (I can’t help it, the errands will simply have to wait a sec)…here is an interesting Finnish 2001 study showing the high plasma concentrations of hesperetin (and naringenin): http://tinyurl.com/ybhajrv Brilliant! Well, I will have to make and drink more citrus-based juices from now on, that is for sure.

Speaking of grapefruit, a few words of warning for those doing chemotherapy: avoid drinking grapefruit juice or eating grapefruit without asking your doctor first. Grapefruit contains compounds that block an important enzyme found in the gut and liver. Simply put, this inhibition causes an increase in blood levels of chemo drugs (or of any other substance, for that matter). That is, when chemo patients drink grapefruit juice, drugs that are usually eliminated quickly via that particular enzyme are able to remain in the bloodstream for longer than warranted. Obviously not a good thing. The reverse is true in the case of poorly bioavailable substances, such as curcumin. Drinking grapefruit juice with curcumin probably helps us absorb it better. 

At any rate, those of us who aren’t on chemo AND aren’t allergic to citrus fruit have absolutely nothing to fear. So, go ahead and drink up! Yum yum.

P.S. For more information on flavanones: http://tinyurl.com/ybsge86 (Here you will also find a helpful chart that distinguishes between flavone, flavonol, flavanone and flavanonol.)


  1. So do we know if it’s the hesperetin itself, or some other ingredient in grapefruit juice, that has the enzyme-blocking properties for those on chemo?

    In other words, how do/can those on chemo take advantage of this hesperetin thingie? 🙂

  2. The compounds that block that particular enzyme (=cytochrome P450 3A4) are called furanocoumarins, which are found mostly in grapefruit juice.
    If you are on chemotherapy, instead of drinking grapefruit juice how about having some orange/other citrus fruit juice? No problem there, UNLESS you are on Velcade, in which case you must be careful. During a recent MM patient seminar that I attended, Dr. Durie said, in fact, that patients on Velcade should not take any vitamin C. I forgot to add that bit to my post yesterday, sorry.
    Clearly, if you are on chemotherapy, it is always best to ask your doctor about possible interactions with citrus fruit or anything else, for that matter. If there are none, and you don’t haven any allergies, then I don’t see any harm in drinking some extra juice. Quite the opposite!
    As for Paul’s question, this MGUS patient must have been in some sort of study, for I cannot find a hesperetin-7-glucoside supplement anywhere. There are various hesperedin-based supplements, but that is all.
    Since I take so many supplements, I must say that it will be a huge relief to swallow some yummy juice and dream of its possible anti-MM benefits.
    Info on bioavailability of hesperetin in juice: http://jn.nutrition.org/cgi/content/abstract/136/2/404

  3. So since there is chemo involved, I was trying to determine if the FCs (furanocoumarins) were the only substance that inhibited CYP3A4, or if other things in the grapefruit juice (like, possibly, the hesperterin) had inhibitory effects also.

    So I found this study:

    What they did was take the FC out of grapefruit juice, and then compared it with regular OJ. They found “The inhibitory effects of both FC-free GFJ and OJ indicated that nonfuranocoumarins (likely flavonoids) were present in sufficient concentrations to inhibit CYP3A4 in the in vitro systems employed.”

    So what I’m reading (I think!!!) is that furanocoumarins are the *main* culprit, but that other substances – probably flavonoids and thus possibly hesperterin – also inhibit this CYP3A4 thing. So, other juices, and hesperterin as an extract, could also be problematic for chemo-takers. Or, is it enough to make a difference? Because the warnings have always been about GF juice, not OJ . . .

    Then I came across this study here:
    http://www.ualberta.ca/~csps/JPPS4(3)/S.Wanwimolruk/grapefruit.htm that tested other components in grapefruit juice, and found that “more than one component present in grapefruit juice may contribute to the inhibitory effect on CYP3A4.”

    First, they studied flavones in GFJ: “At a concentration of 100 uM, flavone (without any hydroxyl group) had little effect, and apigenin (with 3 hydroxyl groups) caused 30-37% inhibition. In contrast, morin and quercetin (with 5 hydroxyl groups) produced 34-41% and 55-65% inhibition respectively, and myricetin (with 6 hydroxyl groups) had 78-94% inhibition (Table 1). The inhibitory potency appeared to be in order from flavone < apigenin < kaempferol < chrysin < morin < fisetin < quercetin < myricetin.” So what does this mean for those on chemo who are also taking, say, quercetin (or apigenin via parsley) supplements? Could they possibly be harmful?

    I noticed that our friend hesperterin was not mentioned, but then realized that was because it is a flavanone, not a flavone (thanks for that link Margaret!) They looked at flavanones and discovered this: “At low concentration (10 uM) of the flavanones, there was no inhibitory effect, except for galangin, naringin, and prunin. When the concentrations of the flavanones were increased to 100 uM and 200 uM, all compounds (except narirutin) inhibited the activity of CYP3A4. Two flavanone glycosides naringin and neohesperidin produced less inhibitory effect than their corresponding flavanones naringenin and hesperetin. At 200 uM concentration, hesperetin, and naringenin caused a similar extent of inhibition ranging from 47 to 64%.”

    So it seems hesperetin itself can cause Mr. Enzyme to be inhibited. The question is, is it enough to be worried about (for those drinking, say, OJ), and does the conversion to H7F reduce its inhibitory effect?

    I am in way over my head here, but for some reason this strikes me as important, although I don’t understand how: “It is known that the 7-hydroxyl group of flavonoids is the first to dissociate and is thus the most likely site of attack by the peroxy radical (30). Similar differences were observed between hesperidin and hesperetin. The IC50 value of hesperidin was 3.7-fold higher than that of hesperetin.”

    Finally the study said “Very little hesperidin (up to 16 mg/L or 26 uM), neohesperidin (up to 10 mg/L or 16 uM), and hesperetin (up to 3 mg/L or 10 uM) have been detected in grapefruit juice” which I found interesting.

    So, more questions as a result :). This is so over my head. I shoulda gone to med school!

    PS I think the supplement is available in Japan.

  4. Grapefruit and grapefruit juice are verboten for patients taking Lipitor also, but the explanation I was given is that the two DO THE SAME THING and it is overkill to take both, which causes other problems.
    Some mm induction chemo patients reach complete or nearly complete response and then have stem cells harvested and are faced with a situation not unlike smoldering. They can
    1) just go off chemo and wait until numbers rise and then zap everything for a SCT
    2) stay on lower dose maintenance and watchful waiting, then zap & SCT as needed.
    3) have the autologous SCT right away ( theory that first response is the best you will ever get)
    So I think this info could be very helpful to patients doing # 1 but they might want to go with OJ. Our smoothie recipe calls for a third or fourth of a can of frozen OJ, no water added. several other great mm-bashing ingredients. I can post it if anyone is interested.

  5. Margaret, thanks for that link on the hesperetin study in your comment above. I was able to read the full paper. To summarize, orange juice contains mostly hesperidin. Orange juice prepared with hesperetin-7-glycoside was roughly three times more effective (time average) in producing hesperetin in the plasma than regular orange juice. Still, regular orange juice is not bad, you will just have to drink 3 times as much of it for a given level of hesperetin.

    But also, there was a distinct difference in the rate of absorption. The modified 7-glucoside produced a high peak within the first few hours, and hesperetin disappeared quickly after that. The high dose regular orange juice didn’t peak until much later and hesperetin stayed in the plasma much longer. This might conceivably be advantageous.

    The reason for the difference is that hesperidin wasn’t broken down until it reached the large intestine, where presumably resident bacterial flora did the job. So maybe eating yogurt containing live bacterial colonies would be a good idea to go along with the orange juice.

  6. Tony V. comment indicates yogurt aids the efficacy of orange juice. Perfect. Here’s the smoothie recipe we brought home from St. John USVI many years ago, with adaptations. Everything in it has relevance for mm patients and/or those on chemo.

    Throw a handful of ice cubes into the blender with some frozen fruit (raspberries, cherries, strawberries, blue berries, what ever) a cup, more or less. Chop on the ice setting.
    For the rest of the ingredients, blend as you go. The order may depend on your blender, some require the liquid ingredients earlier or later to get things moving.
    Add a banana and a big chunk of frozen OJ (Calcium enriched) right out of the can, maybe 1/4 to 1/3 of the can.
    Add 100 percent fruit juice, we like pomegranate, cranberry, or grape) about 1/3 – 1/2 cup.
    Add a cup of yogurt (raspberry vanilla, or any flavor you like that has good acidophilus content – I like Activia vanilla, also I sometimes add the contents of a capsule of powdered acidophilus/probiotics because my patient takes some antibiotics due to compromised immune system.

  7. Hi Margeret, did you hear anything about the hesperidin, especialy the planned trial? My experience with it. I got thr hesperidine from japan and took it for 1 year togethe with curcumin. After I stopped the intake because it went out my numbers rose. (IGA SMM). Perhaps interesting. Best regard and hope you’re doing well, Thomas

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