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Another Bad Effect of Antioxidant Supplements

It’s been increasingly clear that the widespread marketing of antioxidants as vital health-giving nutrients is often mistaken. Taking antioxidants reduces the cellular effects of exercise, and interferes with many forms of cancer treatment (both of which effects are exactly the opposite of the popular conceptions of what should be happening). And now comes word that the same problem seems to exist with the leading tuberculosis drug in the world, isoniazid.

A recent clinical trial in South Africa pointed out some potential trouble. This was a study of a popular dietary supplement (Sutherlandia), a botanical preparation which is apparently widely used in many parts of Africa for infections and general health. It’s widely taken by HIV-positive patients in South Africa, but this is apparently the first controlled trial to see if it has any effect. Unfortunately, it appears to do nothing for HIV at all (viral loads and T-lymphocyte counts did not change). But what did happen was that two of the participants developed active tuberculosis, even though they were taking isoniazid as preventative therapy. The authors proposed that the antioxidant effects of the supplement interfere with isoniazid’s mechanism of action, which is widely believed, on a great deal of evidence, to be oxidative activation with release of nitric oxide and other reactive species. They also suggested that other antioxidant supplements should be studied to see if they have similar effects.

Here’s a paper from a group at Missouri following up on this. Sutherlandia extracts do indeed seem to reduce the production of reactive oxygen species, and reduce gene expression markers of oxidative stress. According to the labels on the juice bottles and nutrition bars, the end-caps in the vitamin aisles, and the blurbs on the popular magazine covers, these should all be great things. But they’re not, or certainly not always – your response to infection and other kinds of cellular stress depends on reactive oxygen species and signaling thereof, and just blocking it wholesale is a bad idea. This certainly doesn’t seem to have penetrated into the popular culture, which is apparently All Antioxidants, All The Time, but it should.

Update: a colleague points out that Sutherlandia is also a known CYP3A4 inducer. In rats it shows a definite interaction with nevirapine via this mechanism, and in humans it increases the clearance of atazanavir. Not what you want among patients taking antiretroviral cocktails, for sure. . .

26 comments on “Another Bad Effect of Antioxidant Supplements”

  1. Lane Simonian says:

    Reactive oxygen species and reactive nitrogen species are part of a host response against viral and bacterial infections, but they can also lead to an over response damaging tissues, for instance. Chemotherapy and radiation therapy also use reactive oxygen species and reactive nitrogen species to kill cancer cells, but they can also kill surrounding cells.

    The other option is to carefully limit the production of ROS and RNS in certain disease states, whereas one should go all out with antioxidants in other disease states.

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2248324/

    1. tangent says:

      Surrounding cells? They can kill them? My cells?

  2. luysii says:

    Medicine is full of stuff like this. The use of supplemental female hormones to prevent heart attack and stroke (based on a large number of naturalistic studies) turned out to be a disaster, with more of same in those receiving estrogen and progestin. A trial of antioxidants (vitamin E derivatives mostly) to prevent lung cancer in those at high risk for it, resulted in MORE lung cancer in those taking the antioxidants. For details see — https://luysii.wordpress.com/2011/10/13/the-risks-of-risk-reduction/

    1. Lane Simonian says:

      One has to be careful with this line of argument. The reason why certain forms of Vitamin E increase lung cancer risk for smokers is because in certain circumstances it can act as a pro-oxidant.

      http://atvb.ahajournals.org/content/atvbaha/21/6/1029.full.pdf

      1. spatz says:

        How many “forms of Vitamin E” are there???

        1. Lane Simonian says:

          There are eight forms of Vitamin E.

          http://www.juvenon.com/the-eight-faces-of-vitamin-e-0903/

  3. Biggie Mac says:

    Could RONS be part of Alzheimer’s disease? The amyloid theory seems to be missing a beat.

    1. Lane Simonian says:

      I am not sure if you are pulling my leg, but this is what I have been arguing for nearly a decade.

      https://www.ncbi.nlm.nih.gov/pubmed/9092586

    2. Anon says:

      Don’t feed the troll!

      1. steve says:

        So then South Africans that have been taking Sutherlandia should be protected from Alzheimer’s, a perfect experiment!

        1. Lane Simonian says:

          Polyphenols do not provide absolute protection against Alzheimer’s disease but they may prevent or delay the onset of the disease.

          https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3024594/

          https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4705783/

  4. loupgarous says:

    This paper treats a related issue, radioprotection. The author has a good discussion of free radical scavengers such as WR-1065 and its prodrug amifostine, which is thought to be hydrolyzed to its bioactive metabolite more in nonmalignant cells because of higher alkaline phosphatase levels and higher pH than in malignant cells, so that tumors are less protected from radiation damage. Using prodrugs of antioxidants which only become active metabolites when and where they’re needed is something to look at (obviously a non-trivial task, admittedly).

    Nanodelivery has been looked at from the other end, , delivering cytotoxic agents which are taken up more by target organs such as brain and bone (something that might have also helped odanacatib go more often where it was needed and not where it could hurt non-target tissues).

    Antioxidants probably shouldn’t be used systemically, something which might be true of a large number of drugs. Targeting ought to extend not just to activity in a certain type of tissues, but developing ways to deliver drugs so that off-target effects are reduced (by either developing drugs taken up preferentially by the target tissue or prodrugs which become active metabolites more often in the target tissue).

  5. Tired says:

    Lane Simonian – You post ad nauseam about your theories for Alzheimer’s. Bless you. Most of us see your links and roll our eyes when we read them because we’ve actually worked in drug discovery. The drug discovery world is just filled with great theories. And trust me, we can find papers (reports) that support our theories without flaw…….as you do.

    And my mother-in-law died of Alzheimer’s disease on Monday. I didn’t promise my wife that your bull***t ideas would save her either because I knew they were just that.

    As someone who worked 30 years in drug discovery, shut up. You’re not going to convince anyone on a blog with an in vitro, crap in vivo, even crappier human study that are all hopelessly flawed, etc. that you’ve solved Alzheimer’s.

    Whatever. Just put your ideas into a human clinical study that shows efficacy (real efficacy) and then get your prize.

    Drug discovery doesn’t work the way you’d like. Theories are perfect until the hard data of a failed clinical trial gives you some humility.

    1. Lane Simonian says:

      I am sorry that your mother-in-law died of Alzheimer’s disease.

    2. Me says:

      Agreed – condolences.

  6. fajensen says:

    One should probably not take any sort of medication at all unless one is diagnosed with something treatable, where the medication really will have an effect.

    We have, I believe, too many people taking “maybe this will be good for you”-drugs like Antidepressants, Statins and Antioxidants. Only to find out later that in the best case the money was wasted, or worse, that the mediation made overall health worse.

    I certainly see a pattern forming with my age group, 50’s, that they acquire one “small” thing like elevated blood pressure, depression, something with cholesterol. Then they get medication for that, then side effect slowly show up, which are medicated, and suddenly their breakfast array of pills looks like that of an AIDS patient.

    I think what happens is the same process with addiction to hard drugs – the drugs move ones body’s set-point to another equilibrium, which relies on the drug being present, then it gets hard to not use the medication because the body now has to adjust back and the new set-point might not be the optimum, “as evolved”, one

    Sure, take what the doctor say. Then stop taking it whenever possible (of course based on clinical measurements). I know some people where the cholesterol thing and blood pressure was eventually solved by exercise, the medication allowed them to exercise in the first place.

    1. Me says:

      *I know some people where the cholesterol thing and blood pressure was eventually solved by exercise, the medication allowed them to exercise in the first place.*

      I do wonder how many of these types of symptoms can be fixed by diet/exercise in the 50’s age range.

      1. Slurpy says:

        It was actually the opposite for me. I started doing martial arts, a few months into it I had to go in for an injury, and decided to get a physical while I was there (healthy male in my mid-30s). We determined I had high blood pressure, she put me on a medication to work with it, and it caused shortness of breath (and therefore dizziness) around the 30th burpee and the rest of the hard cardio. I had to stop taking it because I could only do about half the warmup before wanting to pass out, let alone make it through an hour and a half of jumping around and trying to not get punched in the face.

  7. Morten G says:

    Antioxidants were proposed to be the mechanism behind the epidemiological correlation between intake of fresh vegetables and good health. Clinical studies haven’t backed it up. Moving on.

  8. Janex says:

    It’s too bad that antioxidants are now showing all of these negative effects. Before these research studies began surfacing I had put them down as effective placebo cure-alls which met my criteria. 1. Do no harm and 2. Don’t break the bank. It seems like these are now failing the first criteria. Too bad, good placebos are useful.

  9. MoMo says:

    You all should stop picking on Lane as his interpretations are just as valid as anyone else’s, and we all know how well Alzheimers research has gone so far in Medical history.

    And drug-antibiotic interactions have been studied for decades, although this is the first time Useless-Supplement Drug Interactions have been detailed.

    And antioxidants and their negative effects have been noted for decades. I sat in a pyramid vitamin sales presentation in Newton filled with wide-eyed monied professionals looking for the fountain of youth, and when I asked about things like oxidative burst and phagocytosis the scammers just stared at me like confused dogs.

    And dogs they are. You by the ticket, you take the ride.

    1. Mark Thorson says:

      No, Lane is a crank. Picking on him is like shooting rats. Nothing wrong with that.

      This is not the first time supplement-drug interactions have been studied. There’s considerable literature on the interaction between St. John’s Wort and many drugs. Something in SJW activates the steroid and xenobiotic receptor (SXR), which in turn up-regulates major drug-clearance mechanisms such as the transporter P-glycoprotein and the metabolizer CYP3A4. This has caused among other things failure of birth control drugs and failure of suppression of organ rejection using cyclosporin.

      SJW is not the only SXR agonist in supplements, though it might be the most powerful and certainly is the best documented. Curcumin from tumeric is also an SXR agonist. Probably not a problem at the level which can be consumed from food like curries, but isolated curcumin supplements may indeed be a risk. Also, the tocotrienols (used for their vitamin E activity) are SXR agonists, even though the similar tocopherols are not. The recent fad of using tocotrienols as supplements may have adverse consequences which will not become apparent until we’re some ways down the road.

  10. Anonymous says:

    Oxygen Radical Absorbance Capacity (ORAC). The US Dept of Agriculture used to maintain an ORAC table of various foods that would then be used by companies to hype their offerings to the hoi polloi. However, … “In 2012 USDA’s Nutrient Data Laboratory (NDL) removed the USDA ORAC Database for Selected Foods from the NDL website due to mounting evidence that the values indicating antioxidant capacity have no relevance to the effects of specific bioactive compounds, including polyphenols on human health. … There is no evidence that the beneficial effects of polyphenol-rich foods can be attributed to the antioxidant properties of these foods. The data for antioxidant capacity of foods generated by in vitro (test-tube) methods cannot be extrapolated to in vivo (human) effects and the clinical trials to test benefits of dietary antioxidants have produced mixed results. We know now that antioxidant molecules in food have a wide range of functions, many of which are unrelated to the ability to absorb free radicals.”

    URL: https://www.ars.usda.gov/northeast-area/beltsville-md/beltsville-human-nutrition-research-center/nutrient-data-laboratory/docs/oxygen-radical-absorbance-capacity-orac-of-selected-foods-release-2-2010/

  11. MoMo says:

    “We know now that antioxidant molecules in food have a wide range of functions, many of which are unrelated to the ability to absorb free radicals”- USDA

    Yes Anonymous, we should believe everything the US government tells us, like back in the 50’s when Eleanor Roosevelt was hawking margarine for its health benefits- we all know how that turned out.

    Now they removed ORAC values and lists from their website? Sounds like the work of lobbyists for the Processed Food Industry. Follow the money Anon, follow the money.

  12. Vader says:

    MoMo,

    “Yes Anonymous, we should believe everything the US government tells us, like back in the 50’s when Eleanor Roosevelt was hawking margarine for its health benefits- we all know how that turned out. ”

    It’s one thing to say we shouldn’t believe everything the US government tells us. I find that indisputable.

    But it’s another thing to say we shouldn’t believe anything the US government tells us.

    Since you don’t actually give us any reason we should disbelieve the USDA conclusion that ORAC was useless, it seems to me that you are inviting us to do just that, without actually dirtying your own hands by making that enormous leap in logic yourself.

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