Talk:Antioxidant

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[edit] Work towards consensus within guidelines

OK, people do not all agree with this peer-reviewed meta-analysis that has published in a major medical journal. The two guidelines that apply here are WP:Attribution and WP:Undue weight. I see the section below as giving undue weight to non-peer reviewed opinion articles over a major piece of high-quality research (as defined by the Attribution guidelines). However, these opinions should be noted, so what about the revised formulation below as a compromise? TimVickers 18:37, 23 March 2007 (UTC)

Original

These harmful effects may also be seen in non-smokers, as a recent meta-analysis including data from approximately 180,000 patients showed that β-carotene, vitamin A or vitamin E supplementation is associated with increased mortality.[132] However, this meta-analysis found no significant effect from vitamin C supplementation on mortality. This study has been criticized as being flawed. Jeffrey Blumberg, Director of the Antioxidants Research Laboratory at Tufts University in Boston, Massachusetts, says: "One of the major premises of doing such a meta-analysis is that the studies should be comparable…here, they looked at primary prevention, treatment, old people, young people, smokers, nonsmokers. Only when they used their own criteria of what was good and what was bad were they able to show an increase in all-cause mortality."[1] Meir Stampfer, Professor of Nutrition and Epidemiology at the Harvard School of Public Health says: "This study does not advance our understanding, and could easily lead to misinterpretation of the data."[2]

Compromise wording

These harmful effects may also be seen in non-smokers, as a recent meta-analysis including data from approximately 180,000 patients showed that β-carotene, vitamin A or vitamin E supplementation is associated with increased mortality.[132] However, this meta-analysis found no significant effect from vitamin C supplementation on mortality. The conclusions and methodology of this study have been controversial,[3][4] but its conclusions are consistent with a previous meta-analysis that looked at the effects of antioxidants on people with colon cancer.(Link)

It's not only the conclusions that are controversial, but the methodology of the study. It was a flawed study. And, respected scientists are asserting that it's a flawed study. Those people should be named. Regulations 18:50, 23 March 2007 (UTC)

If you read the guidelines, you will see that it would be inappropriate to give non-peer reviewed opinions more weight than a piece of peer-reviewed research that is of high quality (as defined by Wikipedia). Taking your comments into account, I have revised the proposed new version. Comments? TimVickers 18:59, 23 March 2007 (UTC)

You're still not addressing the fact that scientists are claiming the study was flawed. Noting that they claim this is not giving them more weight than the peer-reviewed research. What makes you think it's giving them more weight? Those scientists who claim this are their peers too, you know? Regulations 19:33, 23 March 2007 (UTC)
Notice that you're giving more weight to that study than it deserves, because there is a whole list of studies that disagree, as can be found in that article I showed you. The weight of the evidence is in favor of anti-oxidants. Regulations 19:45, 23 March 2007 (UTC)

As I'm sure you are aware, the function of meta-analyses is to look at all the clinical trials in an area and bring this together into an overall picture. If you go to [PubMed] and search for "Antioxidants" with the limit set for "type of article - Meta-analysis" you get a list of all the recent meta-analyses on this subject. Of these analyses, none saw protective effects of dietary antioxidants and several, as this section of the Wikipedia article comments, saw harmful effects. This is the data. To reflect this accurately in one sentence - "There is no reliable evidence that antioxidant supplementation is benificial in healthy adults, and some evidence that it is harmful."

As to the question of undue weight the first sentence of this policy reads "NPOV says that the article should fairly represent all significant viewpoints that have been published by a verifiable source, and should do so in proportion to the prominence of each." Meta-analyses in peer-reviewed scientific journals are the highest-quality source on the health effects of drugs there is, therefore we should give these far more weight than the opinion articles on news websites and dietary supplement industry press releases that you have cited. Please understand that this is not my personal opinion, I am just trying to reflect the policy of Wikipedia in this article's discussion of the various sources on this topic. TimVickers 21:03, 23 March 2007 (UTC)

For more information from non-nutracutical industry sources. See the following links:
I've added a note to the discussion of this review pointing out that the effect they detected was not seen in the French SU.VI.MAX trial. This might deal with our problem over giving undue weight to opinion articles, as this trial was peer-reviewed and discussed in a previous section. TimVickers 01:16, 28 March 2007 (UTC)

After reading this Discussion first, I revised the paragraph on the JAMA meta-analysis to include a summary by the editor of Nutraceuticals World. Although an industry publication, this online news magazine is recognized as a high standard and presents a reasonable view. The content of my revision was simply to point out the JAMA report's obvious weaknesses which are apparent to anyone -- clinical scientist, statistician or layperson. My revision follows between the lines:

___ These harmful effects may also be seen in non-smokers, as a recent meta-analysis including data from 68 separate clinical trials of 232,606 patients showed that β-carotene, vitamin A or vitamin E supplementation was associated with increased mortality[5], However, this meta-analysis found no significant effect from vitamin C supplementation on mortality, and its conclusions have been questioned due to the wide heterogeneity of patients already ill with varied diseases studied in different trial designs, treatment dosages and durations[6]. ___

I think this is a fair view. Based on the discussion above -- which shows good debate in need of a conclusion -- my revision is a reasonable compromise, neither refuting the higher-quality JAMA citation nor being too strong in opposition with this one.

Also, I made other syntax changes that section needs, and feel they should be restored. --Paul144 02:04, 28 March 2007 (UTC)

I'm not sure that's a fair assessment and it is a non-peer reviewed article with an obvious bias problem. From the paper itself - The present review follows the Cochrane Collaboration method and is based on the principles of our peer-reviewed protocol and review on antioxidant supplements for gastrointestinal cancer prevention. We included all primary and secondary prevention trials in adults randomized to receive beta carotene, vitamin A, vitamin C, vitamin E, or selenium vs placebo or no intervention. Parallel-group randomized trials and the first period of crossover randomized trials were included.17 Trials including general or healthy populations were classified as primary prevention. Trials including participants with specific disease were classified as secondary prevention. We excluded tertiary prevention (treatment) trials, like trials on acute, infectious, or malignant diseases except nonmelanoma skin cancer."
The meta-analyses seem evenly split between seeing no effect on mortality and seeing a harmful effect, as I noted above. Look for example at PMID: 16842454, PMID: 12804424 PMID: 12814711 and PMID: 15537682. This section does need to be rewritten and expanded, but these other meta-analyses should also be added. TimVickers 02:29, 28 March 2007 (UTC)

How about:

"These harmful effects may also be seen in non-smokers, as a recent meta-analysis including data from approximately 180,000 patients showed that β-carotene, vitamin A or vitamin E supplementation is associated with increased mortality but saw no significant effect from vitamin C.[7] These results are consistent with some previous meta-analyses that suggested that Vitamin E supplementation increased mortality, PMID: 15537682 and that antioxidant supplements increased the risk of colon cancer.PMID: 16842454 However, the results of this meta-analysis are inconsistent with other studies such as the SU.VI.MAX trial, which suggested that antioxidants have no effect on cause-all mortality,[8]PMID: 12804424"

That's better, but I feel fair-minded doubt has to be stated about the original meta-analysis in JAMA conducted on such a diversity of clinical trial groups with different experimental designs. The statement I used should be considered: "its conclusions have been questioned due to the wide heterogeneity of patients already ill with varied diseases studied in different trial designs, treatment dosages and durations".

The JAMA paper states 68 randomized trials with 232,606 participants (385 publications), a set of data making conspicuous the variability inherent in this meta-analysis, even raising questions whether it was a valid meta-analysis.

A premise in meta-analysis (Wikipedia definition) is that it "combines the result of several studies that address a set of related research hypotheses", allowing one to conclude then that JAMA report was inevitably flawed. Among many variables, the "related hypotheses" are only those addressing antioxidants with mortality, whereas "the wide heterogeneity of patients already ill with varied diseases studied in different trial designs, treatment dosages and durations" describes confounding multiple variables making the JAMA report's conclusions doubtful.

Not acknowledging this interpretation dismisses the report's obvious weaknesses, perhaps misleading visitors to this Wikipedia page in search of an alternate interpretation.

We should not be so strict that a publication in JAMA is irreproachable. The industry voices critiquing the JAMA study have been reasoned and their facts are worthy to state in the Antioxidant Article that its design and conclusions are questionable. --Paul144 03:59, 28 March 2007 (UTC)

No, I don't agree. This JAMA paper is certainly not "obviously flawed". A meta-analysis takes data from multiple trials and re-analyses it, either to test the same hypothesis addressed in the original studies, or a new hypothesis. The method followed in this JAMA paper is a standard in the field and are described here. Describing the Cochrane protocols for meta-analyses as "obviously flawed" is simply incorrect. I am happy to put this finding in context with other equally-valid meta-analyses (following similar protocols). Perhaps if you found some meta-analyses that demonstrated positive results of antioxidants this would be a path out of this impasse? If such positive studies exist, they would balance the negative findings. As the Wikipedia WP:Undue weight policy states.

I think you're in the minority defending the JAMA report as unflawed. The key point is that, while appropriate meta-analysis methods were applied according to the Cochrane protocols, the choice of what disease groups to include were obviously not -- the authors grouped 1) unrelated diseases, 2) patients who were both already morbid with their illnesses and those that were healthier, 3) a wide range of doses of antioxidants, 4) a wide range of study durations, etc. This is poor meta-analysis design and is flawed.

You seem entrenched and are not finding a collaborative, balanced position. I think you should remove yourself from this discussion and allow the wiki process of checks and balances for revision of the article. --Paul144 08:58, 28 March 2007 (UTC)

Disagreements over whether something is approached the Neutral Point Of View (NPOV) way can usually be avoided through the practice of good research. Facts (as defined in the A simple formulation section above) are not Points Of View (POV, here used in the meaning of "opposite of NPOV") in and of themselves. A good way to build a neutral point of view is to find a reputable source for the piece of information you want to add to Wikipedia, and then cite that source.
Industry publications are not reliable sources. Adding non-peer reviewed criticisms from people with an obvious bias to this article is deeply unwise and directly contradicts Wikipedia policy - please read WP:Undue weight. TimVickers 04:41, 28 March 2007 (UTC)

I don't agree with your method of excluding an industry source more because it's not from a typical scientific method published in a peer-reviewed journal, rather than listening to the reasonable objections raised to the JAMA article within the publication like the Nutraceuticals World editorial (which would have been peer-reviewed).

Here is one considered position opposing the JAMA report[1] and another from several individuals simply voicing, as I am, that the JAMA study was not the best-designed meta-analysis, indicating that its conclusions should be tempered with other points of view, including those of Dr. Alex Schauss, a scientist who publishes in peer-reviewed literature[2].

If you can't see this, Tim, then I propose we remove the section about the JAMA study in the Antioxidant Article all together, and wait a few months for further analysis of its validity and additional counterpoints to be presented. --Paul144 08:58, 28 March 2007 (UTC)

I probably appear intransigent here as I am bound (as are you) by Wikipedia's policy. To quote directly from the relevant section "NPOV says that the article should fairly represent all significant viewpoints that have been published by a verifiable source, and should do so in proportion to the prominence of each." If Nutracuticals World or NPIcenter are indeed peer-reviewed journals, what is their peer-review process? are they listed in Medline? what is their impact factor? I will be happy to add material from these sources if they are indeed of high quality. However, the onus is on you to show that these sources pass WP:Attribution. This problem would be very easily resolved if you could find some peer-reviewed meta-analyses or randomised double-blind clinical trials that demonstrated positive health effects for antioxidant supplementation. As the policy says "Disagreements over whether something is approached the Neutral Point Of View (NPOV) way can usually be avoided through the practice of good research." TimVickers 15:41, 28 March 2007 (UTC)
To try to help us come to agreement here, I've asked for some input from the Wikipedia:Mediation Cabal as well as requesting some other opinions at the Wikiproject Medicine and Wikiproject Pharmacology. TimVickers 16:02, 28 March 2007 (UTC)
  • I have to agree with TimVickers here—we must insist upon the highest-quality peer reviewed sources in medical articles. If there are significant problems with the JAMA article, that will eventually be published in a peer-reviewed journal; we should err on the side of accuracy over a rush to publish, and we must uphold the highest-quality reliable sources. SandyGeorgia (Talk) 16:05, 28 March 2007 (UTC)
It should be noted that, even discounting the potentially serious methodological flaws, in the words of the aforementioned JAMA analysis "The pooled effect of all supplements vs. placebo or no intervention in all randomized trials was not significant." They did further restriction (throwing out an additional 21 trials for being "high bias" through what they admit is a process with some risk of error) before coming to the final conclusion was reached. --71.218.232.238 20:14, 6 April 2007 (UTC)

Good evening! I've decided to take your Mediation Cabal case. If you're still interested in mediation, please read over and respond to my comments at the case page. Looking forward to working with you all. --Moralis (talk) 01:46, 11 April 2007 (UTC)

[edit] Iodine and evolution

Temporary re-location until the formatting and content is worked out. TimVickers 22:05, 14 April 2007 (UTC)

Evolution of dietary antioxidants

The evolution of oxygen-producing cells was probably one of the most significant events in the history of life. Oxygen is a potent oxidant whose accumulation in terrestrial atmosphere resulted from the development of photosynthesis over three billion years ago, in blue-green algae (Cyanobacteria), which were the most primitive oxygenic photosynthetic organisms. Brown algae (seaweeds) accumulate inorganic iodine to more than 30,000 times the concentration of this element in seawater, up to levels as high as 1-3 % of dry weight (77, 78). Protective endogenous antioxidant enzymes and exogenous dietary antioxidants helped to prevent oxidative damage (79, 80). In particular, mineral antioxidants present in the primitive sea, as some reduced compounds of Rubidium, Vanadium, Zinc, Iron, Cuprum, Molybdenum, Selenium and Iodine, which play an important role in electron transfer and in redox chemical reactions (81). Most of these substances act in the cells as essential trace-elements in redox and antioxidant metallo-enzymes. When about 500 million years ago plants and animals began to transfer from the sea to rivers and land, environmental deficiency of marine mineral antioxidants and iodine, was a challenge to the evolution of terrestrial life (82).

Terrestrial plants slowly optimized the production of “new” endogenous antioxidants such as ascorbic acid, polyphenols, flavonoids, tocopherols etc. A few of these appeared more recently, in last 200-100 million years ago, in fruits and flowers of angiosperm plants. In fact Angiosperms (the dominant type of plant today) and most of their antioxidant pigments evolved during the late Jurassic period. Plants employ antioxidants to defend their structures against reactive oxygen species (ROS) produced during photosynthesis (83).

The human body is exposed to the very same oxidants, and it has also evolved effective antioxidant systems. Plant-based, antioxidant-rich foods traditionally formed the major part of the human diet, and plant-based dietary antioxidants are hypothesized to have an important role in maintaining human health. Moreover, chordates, the primitive vertebrates, began to use also the “new” thyroidal follicles, as reservoir for iodine, and to use the thyroxine in order to transport antioxidant iodide. Iodide is one of the most abundant electron-rich essential element in the diet of marine and terrestrial organisms. Iodide, which acts as a primitive electron-donor through peroxidase enzymes, seems to have an ancestral antioxidant function in all iodide-concentrating cells from primitive marine algae to more recent terrestrial vertebrates for their better adaptation to terrestrial environment: fresh waters, atmosphere, gravity, temperature and diet (84).


REFERENCES

77. Venturi S, Venturi M. Iodide, thyroid and stomach carcinogenesis: evolutionary story of a primitive antioxidant? Eur J Endocrinol. 1999 Apr;140(4):371-2. N PMID: 10097259

78. Küpper FC, Feiters MC, Meyer-Klaucke W, Kroneck PMH, Butler A (2002) Iodine Accumulation in Laminaria (Phaeophyceae): an Inorganic Antioxidant in a Living System? Proceedings of the 13th Congress of the Federation of European Societies of Plant Physiology, Heraklion, Greece, September 2-6, p. 571

79. Küpper FC, Schweigert N, Ar Gall E, Legendre J-M, Vilter H, Kloareg B (1998) Iodine uptake in Laminariales involves extracellular, haloperoxidase-mediated oxidation of iodide. Planta 207:163-171

80. Ar Gall, E., Küpper, F.C. & Kloareg, B. (2004). A survey of iodine content in Laminaria digitata. Botanica Marina 47: 30-37.

81. Cocchi M, Venturi S. Iodide, antioxidant function and omega-6 and omega-3 fatty acids: a new hypothesis of a biochemical cooperation? Progress in Nutrition, 2000; 2 :15-19

82. Venturi S, Donati FM, Venturi A, Venturi M. Environmental iodine deficiency: A challenge to the evolution of terrestrial life? Thyroid. 2000 Aug;10(8):727-9. PMID: 11014322

83. Venturi S. and Venturi M. “Iodine and Evolution”. DIMI-MARCHE NEWS, Dipartimento Interaziendale di Medicina Interna della Regione Marche (Italy), published on-line, Feb. 8, 2004: http://web.tiscali.it/iodio/

84. Venturi S, Donati FM, Venturi A, Venturi M, Grossi L, Guidi A. Role of iodine in evolution and carcinogenesis of thyroid, breast and stomach. Adv Clin Path. 2000 Jan;4(1):11-7. PMID: 10936894

Comments

  1. The references don't establish iodine as a significant contributor to antioxidant defences, compared to thiols or ascorbate.
  2. Metal ions are not antioxidants, if anything they are pro-oxidant species.
  3. After the development of oxygenic photosynthesis, the concentration of reduced metal ions in seawater became negligible.
  4. Fruits and flowers are not photosynthetic tissues, don't you mean leaves?
  5. Antioxidant defences do not differ significantly between humans and other mammals, saying that "the human body" evolved these systems is therefore misleading - this happened much earlier.
  6. What is an "Electron-rich" element?
  7. What do gravity and temperature have to do with this?

TimVickers 02:28, 15 April 2007 (UTC)

69.120.148.70 20:51, 1 July 2007 (UTC)===Response=== Dear Tim,

I now try to respond to your 7 important comments! Excuse-me for my bad English!


The Benzie’s review ( PMID: 14527634 ) is important but it concerns only the “Evolution of dietary antioxidants” in last 10,000 years!

Benzie IF. Evolution of dietary antioxidants.Comp Biochem Physiol A Mol Integr Physiol. 2003 Sep;136(1):113-26.


1.The references don't establish iodine as a significant contributor to antioxidant defences, compared to thiols or ascorbate.


In the text of some reported references iodine seems to be a significant contributor to antioxidant defences, may be more than thiols or ascorbate: See http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?CMD=search&DB=pubmed

Effect of iodide on total antioxidant status of human serum. Winkler R, Griebenow S, Wonisch W.

The antioxidant effect of 15 microM NaI has been found to be approaching the physiologically relevant concentration of ascorbic acid (50 microM).

The problem is that this study used 15 uM iodide, the normal serum concentration of iodide is 100-fold lower link link 2. Therefore if iodide's effectiveness is proportional to its concentration, it is 100-fold less important than ascorbate.

1. It’s correct! but while vitamin C is probably active in all the cells of our body (about 70 kg), iodide, as an antioxidant, is probably active only in iodide-concentrating cells: thyroid cells (colloid substance is extracellular!) salivary glands, mucous cells of gastric mucosa, choroid plexus, epidermis, ductular cells of mammary gland only in pregnancy and lactation: about 20-40 grams! It is more than 30,000-fold than ascorbate.

And in the other hand:In 2001, Hays reported in “Thyroid ” journal that “It is surprising that the precise total iodine content of the human body remains uncertain after many years of interest in iodine metabolism … and that extra-thyroidal iodine pool remains a matter of speculation and also the chemical nature non-thyroidal iodine is unknown.”

In humans, the total amount of iodine seems to be about 25-50 mg and about 50-70 % of total iodine is non-hormonal and it is concentrated, via NIS, in extrathyroidal tissues (Venturi 2000a, b). Other researchers reported higher values: Guy Abraham, M.D., a former professor of obstetrics and gynecology at UCLA, and Donald Miller:

http://www.jpands.org/vol11no4/millerd.pdf


Hays MT (2001) Estimation of total body iodine content in normal young men. Thyroid 11(7):671-5.

So as iodide is only important in a few iodide-concentrating tissues, you can see why I'm hesitant to base the discussion of the evolution of all antioxidant systems around iodine. Out of three paragraphs on the evolution of antioxidants, two are devoted to iodine - this is unbalanced.


2.Metal ions are not antioxidants, if anything they are pro-oxidant species.

Reduced forms of many marine metals seem to be important as electron-donors, as reported in:

Favier A (1991) Les oligoelements en nutrition humaine. In: Les Oligoelements en Medicine et Biologie. Ed Chappuis P. Publ Lavoisier, Paris

You listed zinc, for example, as an antioxidant species. Under what conditions could Zn2+ donate electrons in biological systems?

2. Zinc works in SOD.

Virgili F, Canali R, Figus E, Vignolini F, Nobili F, Mengheri E. Intestinal damage induced by zinc deficiency is associated with enhanced CuZn superoxide dismutase activity in rats: effect of dexamethasone or thyroxine treatment. Free Radic Biol Med 1999; 26 (9-10) :1194-201

Virgili et al. reported that treatment with thyroxine protects from peroxidative intestinal damages, induced by zinc-deficiency in rats .

Zinc works as a cofactor in SOD, it is not an antioxidant any more than histidine is an antioxidant because it is present in the active site of the same enzymes. This has been discussed before for selenium, see the talk archive Talk:Antioxidant/Archive_1#Selenium. TimVickers 15:12, 16 April 2007 (UTC)


3.After the development of oxygenic photosynthesis, the concentration of reduced metal ions in seawater became negligible.

I don’t know to respond to this comment!

Take iron for example, the concentration of Fe2+ drooped precipitously when the atmosphere became oxidising - now it is less than 1 ng/ml in seawater.link.
Of course ! metal ions were oxidized both by intracellular ROS and by atmospheric oxygen.
That's the point I'm trying to make. It might just be your phrasing, but the section above makes it sound like these trace elements are antioxidants. In fact they are at low concentrations and largely oxidised outside cells.


4.Fruits and flowers are not photosynthetic tissues, don't you mean leaves?

Of course, fruits and flowers are not photosynthetic tissues, but I only mean that they are an important source of vegetable pigmented antioxidants.

But the utility of well-known antioxidant vitamins in some chronic diseases has not been recently supported by statistical data, and their benefits in cancer prevention have not been recently confirmed by epidemiological data (Bjelakovic et al. 2004, 2007; Hung et al. 2004; Lin et al. 2005; Sato et al. 2005; Tsubono et al. 2005; Morris and Carson 2003).

In the wide range of antioxidants, it is possible an “evolutionary hierarchy”, where the most ancient might be more essential than the “modern” ones in the developing stages of animal and human organisms.

(Venturi and Venturi 2006). http://web.tiscali.it/iodio/

Deficiency of iodine, as a primitive antioxidant, seems to cause more damage in developing embryos than some other “modern” antioxidants. In fact, in pregnant women I-deficiency causes abortions and stillborns (Dunn and Delange 2001).

Bjelakovic G, Nikolova D, Simonetti RG, Gluud C (2004) Antioxidant supplements for prevention of gastrointestinal cancers: a systematic review and meta-analysis. Lancet 2:1219-28

Bjelakovic G, Nikolova D, Gluud LL, Simonetti RG, Gluud C. Mortality in randomized trials of antioxidant supplements for primary and secondary prevention: systematic review and meta-analysis. JAMA. 2007 Feb 28;297(8):842-57.

CONCLUSIONS: Treatment with beta carotene, vitamin A, and vitamin E may increase mortality. The potential roles of vitamin C and selenium on mortality need further study

Dunn JT, Delange F (2001) Damaged reproduction: the most important consequence of iodine deficiency. J Clin Endocrinol Metab 8:2360-3

5.Antioxidant defences do not differ significantly between humans and other mammals, saying that "the human body" evolved these systems is therefore misleading - this happened much earlier.

According Favier [Favier A (1991) Les oligoelements en nutrition humaine. In: Les Oligoelements en Medicine et Biologie. Ed Chappuis P. Publ Lavoisier, Paris], selenium, iodine and other marine minerals don’t are essential (as antioxidants) for many terrestrial plants. Terrestrial plants had elaborated some new and self-made antioxidants as many polyphenols, carotenoids, flavonoids, tocopherols and ascorbic acid. A few of these appeared more recently, in last 200-100 My, in fruits and flowers of angiosperm plants (Venturi 2004, 2006). In fact Angiosperms (the dominant type of plant today) and most of their antioxidant pigments evolved during the late Jurassic period. Some of these new antioxidants became essential “vitamins” in the diet of terrestrial animals (vitamins C, A, E). According to Coic and Coppenet and Lamand (1991) [ In: Les Oligoelements en Medicine et Biologie. Ed Chappuis P. Publ Lavoisier, Paris], iodine and selenium became no longer necessary to many plants.

I was just commenting on your phrasing, which made it appear that new antioxidant systems evolved in humans.

5. I mean that "the human body" evolved also other different systems from plants antioxidants.

We evolved nothing new. All human antioxidants were present in our animal ancestors. TimVickers 15:12, 16 April 2007 (UTC)


6.What is an "Electron-rich" element?

"Electron-rich" elements are, according my opinion, many atoms which have in their external shell many electrons so as in case of iodide, which has 54 electrons and can give easily one electron to other atoms in fact:

2 I- -> I2 + 2 e- (electrons) = - 0.54 Volt ;

"Reducing" might be a better word, as all elements contain electrons in their outer shell!

7.What do gravity and temperature have to do with this?

I think that many actions of iodine and iodinated hormones are important for bone-strengthen and thermogenic ( in birds and in mammals) actions . A spectacular exemplum of that in amphibian metamorphosis. In fact, iodine and thyroid hormones are necessary in terrestrial living animals ( differently to marine animals) for counteract the gravity and temperature of terrestrial environment.

This section on the skeleton and thermoregulation might be best in another article, as this doesn't seem related to antioxidants.

7. I think you are right!


Thanks for your interest in this, Sebastiano! TimVickers 19:30, 15 April 2007 (UTC)

Thanks for your appreciated comments!

Best regards

Sebastiano Venturi

[edit] Evolution outline

We certainly need a section on this, Sebastiano is quite right that this is a major omission from the article. This is what I would propose as an outline:

  • Origin of life under reducing conditions.
  • Oxygenic photosynthesis as the beginning of oxidative stress.


The evolution of oxygen-producing cells was probably one of the most significant events in the history of life. Protective endogenous antioxidant enzymes and exogenous dietary antioxidants [as Selenium and Iodine (I)] helped to prevent oxidative stress. When about 500 million years ago plants and animals began to transfer from the sea to rivers and land, environmental I-deficiency was a challenge to the evolution of terrestrial life.


  • Evolution of GSH, ascorbate and antioxidant enzymes, mention of iodine if particularly important in cyanobacteria?


Oxygen is a potent oxidant whose accumulation in terrestrial atmosphere resulted from the development of photosynthesis over three billion years ago, in blue-green algae (Cyanobacteria), which were the most primitive oxygenic photosynthetic organisms.


Obinger C, Regelsberger C, Strasser C, Burner U, Peschek CA (1997) Purification and characterization of a homodimeric catalase-peroxidase from the cyanobacterium Anacystis nidulans. Biochem Biophys Res Commun 235:545-552


Obinger C, Regelsberger C, Strasser C, Peschek CA (1997) Scavenging of activated oxygen species in cyanobacteria. 9th International Symposium on Phototrophic Prokaryotes.Vienna, Austria p.142


Gall EA, Küpper FC, Kloareg B (2004) A survey of iodine content in Laminaria digitata. Botanica Marina 47: 30–37



  • Evolution of carotenoids and other plant-specific antioxidants.



A summary report of evolution of some well-known antioxidants


Selenium


Selenium is an antioxidant mineral, greatly present in primitive seawaters and is an essential component of the enzyme glutathione peroxidase in mammals. Selenium is present in cellular peroxidases and deiodinases ( type 1 and 3), which are able to extract electrons from iodides, and the latter iodides from iodothyronines. One family of selenium-containing molecules as glutathione peroxidases (GPx) repairs damaged cell membranes, while another (glutathione S-transferases) repairs damaged DNA and prevents mutations ( Stadtman, ’96). Selenium acts synergistically with iodine. The mono-deiodinase ( type I and type III ) enzymes are selenium-dependent and are involved in thyroid hormone regulation. In this way selenium status may affect both thyroid hormone homeostasis and iodine availability. Several selenoproteins participate in the protection of thyrocytes from damage by H2O2 produced for thyroid hormone biosynthesis. The deiodinase isoenzymes constitute the second family of eukaryotic selenoproteins with identified enzyme function. Deiodinases catalyze the reductive cleavage of aromatic C-I bonds in ortho-position to either a phenolic or a diphenylether oxygen atom in iodothyronine. Trace elements involved in glutathione peroxidase and superoxide dismutases enzymes activities – i.e. selenium, magnesium, copper and zinc, were lacking in some terrestrial iodine-deficient areas selenocysteine (Gladyshev and Hatfield, ’96). From about three billion years ago, prokaryotic selenoprotein families drive selenocysteine evolution. This micronutrient is incorporated into several prokaryotic selenoprotein families in bacteria, archaea and eukaryotes as selenocysteine (Gladyshev and Hatfield, ’96). The selenoprotein peroxiredoxins protect bacterial and eukaryotic cells against oxidative injury. Also selenoprotein families of GPx and deiodinase of eukaryotic cells seem to have a bacterial phylogenetic origin. The selenocysteine-containing form also occurred in other fish, chicken, sea urchin, green algae and diatoms. New selenoproteins are recently (about 200 Mya) developed in mammalians (Castellano et al., 2004; Kryukov and Gladyshev, 2004; Wilting et al. ’97; Zhang et al., 2005). Marine fish and vertebrate thyroid gland have the highest concentra¬tion of selenium and iodine.


Ascorbic acid (Vitamin C)


Ascorbic acid (“Vitamin C” for humans) is a common antioxidant in mammals . Ascorbic acid is a water soluble antioxidant and it exists primarily as ascorbate at physiological pH. Ascorbate is a powerful reducing agent capable of rapidly scavenging a number of ROS. Freshwater teleost fishes also require dietary (vitamin C) in their diet or they will get scurvy (Hardie et al.,’91). The most widely recognized symptom of Vitamin C deficiency in fish is scoliosis, lordosis and dark skin coloration. Terrestrial freshwaters salmonids also show impaired collagen formation, internal/fin haemorrhage, dark colouration, distorted/twisted gill filaments, poor wound repair, increased mortality, reduced egg hatchability. If fishes are housed in seawater with algae and phytoplankton, then vitamin supplementation seems to be less important, presumably because of the availability of other antioxidants in natural marine environment (Hardie et al.,’91). For this reason, we hypothesise that the antioxidant action of ascorbic acid developed in the cell metabolism when, about 400 Mya, animals (fishes) and plants started to adapting themselves to mineral (and iodine) deficient fresh waters of estuary of rivers and land. Like plants, most mammals (with exception of humans and guinea pigs) make their ascorbic acid from glucose and can make glucose from ascorbic acid. Remote ancestors of humans suffered a genetic mutation about 40-45 million years ago and haven't been able to make “vitamin C” since. Therefore living humans need nowadays to get all our “vitamin C” from food. Some scientists think that the loss of our ability to make “Vitamin C” may have caused Homo Sapiens' rapid evolution into modern man (Challen et al., ’98; Benhegyi et al., ’97; Stone, ’79).


Carotenoids and Flavonoids


More than 600 plant carotenoids have been identified in plants but less than 50 are abundant in the human diet. Carotenoids are nutritionally important for normal cell regeneration, plus numerous other health aspects linked to unstable oxygen molecules called free radicals (Packer, ’92; Packer, ’93; Cadenas and Packer, 2002). Lucy and Lichti (1969) reported an interesting electron transfer from vitamin A (and carotenoids) to iodine in cellular membranes, in which iodide ions are formed, where a double bond in retinol (or retinoic acid) is presumably the source of these electrons that are transferred from the vitamin to iodine. Two different mechanisms may be proposed in the present context to account for the effectiveness of very small quantities of vitamin A in vivo.

(1) The electron-deficient products that are formed when the vitamin behaves as a donor have access to a regenerative source of electrons.

(2) Vitamin A interacts with a donor of electrons immediately before, or at the same time as, it donates electrons itself. The electron-acceptor properties of vitamin A, and its interactions with electron-donor substances, may be relevant to the latter possibility.

In both of these theoretical mechanisms electron transfer occurs without the vitamin being destroyed. In fact carotenoids and vitamin A (as iodine/iodide) are both excellent donors and acceptors of electrons. Vitamin A participates catalytically in certain oxidation-reduction reactions that are essential for the normal functioning of organized tissues in vivo, and the physical properties of vitamin A indicate that these reactions may occur on or in membranes. Flavonoids and carotenoids are the biggest group of antioxidant phytochemicals studied.

Some of these pigmented antioxidants form the colors of plants and in particular of fruits and flowers. Flowering plants are Angiosperms, which produce seeds enclosed in fruits and flowers. Angiosperms, the dominant type of plant today, evolved rather recently about 200-100 million years ago from cone-bearing gymnosperms, during the late Jurassic period. So also most of the antioxidant pigments are evolved rather recently. Most of carotenoids are "sacrificial" antioxidants, in other words, carotenoid molecules are not regenerated like other antioxidants, and are degraded in the process of neutralizing free radicals or reactive oxygen species.



  • Evolution of animals dependent on plant-produced antioxidant vitamins.


When about 500-300 Mya some living plants and animals began to transfer from the sea to rivers and land, environmental I-deficiency was a challenge to the evolution of terrestrial life (Venturi 2000a). In fishes, plants and animals the terrestrial diet became deficient in many primitive marine trace-elements, including iodine and selenium.

Terrestrial plants slowly optimized the production of “new” endogenous antioxidants such as ascorbic acid, polyphenols, carotenoids, flavonoids, tocopherols, some of which became essential “vitamins” in the diet of terrestrial animals (vitamins C, A, E). According to Coic and Coppenet (1990) and Lamand (1991), iodine and selenium became no longer necessary to many plants.

In a different way, some chordates, about 500 Mya, began to use also the “new” thyroidal follicles, as reservoir for iodine, and to use the thyroxine in order to transport antioxidant iodide and triiodothyronine into the peripherical cells. Triiodothyronine (T3), the biologically active form of thyroid hormone in vertebrates, became active in the metamorphosis and thermogenesis for a better adaptation to terrestrial fresh-waters, atmosphere, gravity, temperature and diet.

The family of peroxidase enzymes includes mammal, mi¬croorganism, plant, algal, and fungal peroxidases. Some of these peroxidases, known as haloperoxidases, use halide ions (iodide, bromide, and chloride) as natural electron donors, and have an antioxidant function in Cyanobac¬teria (Obinger et al. 1997, 1999; Venturi and Venturi 1999). Taurog (1999) reported that the relation between animal and non-animal peroxidases probably rep¬resents an example of convergent evolution to a common en¬zymatic mechanism.

Broadhurst et al.(2002) and Cunnane (2005) suggested that early Homo sapiens, living around the Rift Valley lakes and up the Nile Corridor into the Middle East, received iodine and n-3 fatty acids from littoral food resources.

Dobson (1998) suggested that Neanderthal man suffered I-deficiency disorders caused by inland environment or by a genetic difference of his thyroid compared to the thyroid of the modern Homo Sapiens. I-deficient humans, like endemic cretins, suffer physical, neurological, mental, immune and reproductive diseases. Iodine has favored the evolution of the nervous system for a better adaptation to terrestrial environment as recently reported by

Cunnane (2005), who suggested that “iodine is the primary brain selective nutrient in human brain evolution.” Cordain et al.(2005) recently reported that the significant changes in diet, that began with the introduction of agriculture and animal husbandry approximately 10,000 years ago, occurred too recently on an evolutionary time scale for the human genome to adjust. In conjunction with this discordance between our ancient, genetically determined biology of hunter-gatherers and fisher-gatherers human societies and the nutritional patterns of contemporary Western populations, many of the so-called diseases of civilization have emerged.

Cordain suggests that iodine deficiency was probably one, among other dietary variations, introduced during the Neolithic and Industrial Periods, which have altered crucial nutritional characteristics of ancestral human diet (simultaneously fiber and polyunsaturated fatty acid contents). The evolutionary collision of our ancient genome with the nutritional qualities of recently introduced foods may underlie many of the chronic diseases of Western civilization.


I think that studies of molecular evolution of primitive antioxidants might provide the basis for further research into “new” active substances against many human chronic pathologies.

Regards, Sebastiano

Comments? TimVickers 15:57, 16 April 2007 (UTC)

Melatonin evidently started out as an antioxidant before it acquired a signaling role. See the relevant page.--68.35.43.82 13:32, 25 April 2007 (UTC)
One of the better (best?) examples of antioxidant evolution might be the sequestration of iron (sometimes with directed H2O2 scavenging) into protein cages, aka ferritin, bacterioferritin, Dps, DpsL, etc. Check PMID 16953567 and PMID 16412514 for background. TheTweaker 14:55, 22 June 2007 (UTC)
Indeed. That's already covered in the third paragraph of the "Overview" section. TimVickers 15:24, 22 June 2007 (UTC)
It's mentioned there, but it's lacking the fact that some ferritins can act as a dismutase. However, my point is that the ferritins should be included in any discussion of antioxidant evolution: the structural and sequence conservation, ubiquity throughout kingdoms, varying catalytic activity etc all make them a good example of the evolution of oxidative stress mechanisms. Persons better familiar with them than I might make the case for them to be one of the oldest and most important antioxidants. TheTweaker 16:43, 22 June 2007 (UTC)


[edit] Selenium as an antioxidant

Selenium is not really an antioxidant. Selenium is a toxic metal. Selenocysteine is an amino acid present in several selenoproteins that have antioxidant functions, but this does not make selenium an antioxidant as other elements are equally important for the function of these enzymes. Selenium is certainly essential for the function of some antioxidants, but I don't really think this makes the element an antioxidant itself. TimVickers 18:31, 16 April 2007 (UTC)

[edit] orphan image: Image:Foods highest in antioxidants.jpg

Hi, I was gonna add Image:Foods highest in antioxidants.jpg to this page 'cause it looks informative (pinto beans? I had no idea..), but since this is an FA under mediation.... I'll just let y'all decide. later... Ling.Nut 05:24, 12 June 2007 (UTC)

Tabular data shouldn't really be presented in an image file (see WP:MOS), but this data might be quite a useful addition to List of antioxidants in food if it were converted to the correct format. TimVickers 14:52, 12 June 2007 (UTC)
I was just trying to find a home for the orphan... if it needs to be converted to a table, I'll leave that task for someone else.. thanks.. Ling.Nut 15:07, 12 June 2007 (UTC)
I'll happily convert it to a wikitable. However, it would be nice to find a "citable" source we can attribute the information to (i.e. an URL, not just "USDA"). Also, is there an unit for "Total antioxidant capacity per serving size"? Fvasconcellos (t·c) 19:38, 12 June 2007 (UTC)
Done, in my sandbox. I'd still like a source and an unit :) Fvasconcellos (t·c) 19:51, 12 June 2007 (UTC)
Added to your sandbox. TimVickers 20:13, 12 June 2007 (UTC)
Excellent! Feel free to move it to its proper location, then. I agree it would be a welcome addition to our List of antioxidants in food. Perhaps on Oxygen radical absorbance capacity as well? Fvasconcellos (t·c) 20:20, 12 June 2007 (UTC)
Done and done. TimVickers 20:33, 12 June 2007 (UTC)

[edit] Redox recycling

"Redox cycling may allow other antioxidants (such as vitamin C) to act as pro-oxidants, counterintuitively promoting free radical formation."

Vitamin C first acts as an anti-oxidant before acting as a pro-oxidant.

I suggest that ", counterintuitively promoting free radical formation" be deleted.

Michael H 34 01:08, 22 June 2007 (UTC) Michael H 34

Pro-oxidants do promote free-radical and ROS production though, what about "...to act as pro-oxidants and promote free radical formation." TimVickers 02:02, 22 June 2007 (UTC)

I think that your sentence is an improvement, but I also think that the word promote is too strong. If all vitamin C were recycled in the same location where it acted as an anti-oxidant, then on a net basis, vitamin C has acted neither as an anti-oxidant or a pro-oxidant. Does there exist a mechanism for safe redox recycling (possibly in the liver - possibly through the action of enzymes)? I don't know.

How about:

The oxidized form of other anti-oxidants (such as vitamin C) may act as pro-oxidants through redox cycling. For example, although free radicals are reduced when vitamin C is oxidized, free radicals may be formed again when the oxidized form of vitamin C is reduced through redox recycling.

(If there exists a mechanism for redox recycling of vitamin C by enzymes, this should be mentioned.)

Best wishes, Michael H 34 21:22, 22 June 2007 (UTC) Michael H 34

It is the reduced form of antioxidants that produce ROS, usually through reduction of metal ions. This is explained in a bit more detail on the pro-oxidant page. TimVickers 22:34, 22 June 2007 (UTC)

Thank you, Tim! I see the light!

I would like to suggest that the following section from the pro-oxidant article, which is perfectly clear, may merit inclusion in this article:

[edit] Anti-oxidant vitamins can also be pro-oxidants

Vitamins that are reducing agents can also be pro-oxidants. Vitamin C has antioxidant activity when it reduces oxidizing substances such as hydrogen peroxide,[9] however, it can also reduce metal ions which leads to the generation of free radicals through the fenton reaction.[10][11]

2 Fe3+ + Ascorbate → 2 Fe2+ + Dehydroascorbate
2 Fe2+ + 2 H2O2 → 2 Fe3+ + 2 OH· + 2 OH−

The relative importance of the antioxidant and pro-oxidant activities of antioxidant vitamins are an area of current research, but vitamin C, for example, appears to have a mostly antioxidant action in the body.[12][10] However, less data is available for other dietary antioxidants, such as polyphenol antioxidants,[13] zinc,[14] and vitamin E.[15]

(I only changed the order of the reactions.)

Best wishes, Michael H 34 23:36, 22 June 2007 (UTC) Michael H 34

[edit] Dangerous Chain Reaction

The third sentence mentions a "dangerous chain reaction" that can be caused by free radicals. The use of dangerous here needs some context for this article and introduction to stand on its own. I don't know what type of danger these radicals may be putting us in, otherwise I would edit it myself. Thanks.

Rewritten to give specific example. TimVickers 02:45, 22 June 2007 (UTC)

[edit] The mechanism shown is incorrect

The scheme "The free radical mechanism of lipid peroxidation." is incorrect. It is the allylic positions that are attacked, not the vinyl C-H.--Smokefoot 23:17, 30 July 2007 (UTC)

Thanks, you're quite right. Is there anything else wrong with the new version? Tim Vickers 23:31, 30 July 2007 (UTC)
The SVG is now fixed. Fvasconcellos (t·c) 00:10, 31 July 2007 (UTC)
The regiochemistry of the allylic oxygenation looks ok - you folks work fast. From March's "Advanced Organic Chem" the homolytic bond dissociation energy for allylic CH (i.e., CH2CHCH2-H) is 361 kJ/mol, vs. 419 for ethane (Et-H) vs 444 for ethene (CH2CH-H). In terms of the presentation, O2 appears at first glance to be a product whereas one might place this reagent over an arrow. Also the same unsaturated lipid is shown twice, which is confusing to me at least. And usually, ROO. is thought to abstract an (allylic) H from another lipid to give hydroperoxide (ROOH) and a new allyl radical, hence the key idea of a radical chain. Finally, while I am at it, the identity of the radical initiator is usually not known, is there really a proposa that its HO.? (O2 is out, I know) This report is indeed very nice and should be well received. --Smokefoot 22:58, 31 July 2007 (UTC)

Is this version clearer? The OH radical is certainly capable of this reaction, although I don't know if it is the most important radical doing this in vivo. I'm basing the figure on scheme 1 of thia review. Thanks again. Tim Vickers 23:21, 31 July 2007 (UTC)

Looks good to me. --Smokefoot 00:42, 1 August 2007 (UTC)
And fixed. Sorry, Tim—I know you want to have a go at Inkscape :D Fvasconcellos (t·c) 02:42, 1 August 2007 (UTC)

[edit] Spelling?

Under health effects (disease prevention): "However, despite the clear role of oxidative stress in cardiovascular disease, controlled studies using antioxidant vitamins have observed no clear reduction in the risk or progression of heart disease.[120] "

Should this be "in the risk OF progression of heart disease"? Otherwise it could suggest that the findings relate to the risk of getting heart disease.81.104.186.166 17:46, 5 November 2007 (UTC)

I've reworded this to read "However, despite the clear role of oxidative stress in cardiovascular disease, controlled studies using antioxidant vitamins have observed no reduction in either the risk of developing heart disease, or the rate of progression of existing disease." Tim Vickers 17:51, 5 November 2007 (UTC)
I'm not sure that this is what the study actually shows. Their conclusion is as follows - "CONCLUSION- Our meta-analysis showed no evidence of a protective effect of antioxidant or B vitamin supplements on the progression of atherosclerosis, thus providing a mechanistic explanation for their lack of effect on clinical cardiovascular events." It mentions nothing about developing heart disease. I'd suggest rewording it to "However, despite the clear role of oxidative stress in cardiovascular disease, controlled studies using antioxidant vitamins have observed no reduction in the rate of progression of atherosclerosis."81.104.186.166 01:59, 7 November 2007 (UTC)
I was basing this on the last paragraph of the discussion:
"Vitamin-mineral supplements are widely used in the United States to prevent atherosclerosis and other chronic diseases (52). This use, however, is not supported by scientific evidence. Randomized trials assessing clinical endpoints indicate that ß-carotene and vitamin E supplements may increase mortality, whereas B vitamin supplements do not prevent cardiovascular events. There is already enough evidence to recommend against using these supplements for cardiovascular disease prevention. Our meta-analysis showed that antioxidants do not prevent the development of atherosclerosis, thus providing a mechanistic explanation for the lack of effect of these supplements on clinical events. Furthermore, our meta-analysis found no evidence to support the use of vitamin-mineral supplements to prevent restenosis after PTCA. Although future research may identify a role for supplements in chronic disease prevention, antioxidants or B vitamins should not be used at present for cardiovascular disease prevention." Tim Vickers 02:07, 7 November 2007 (UTC)
The introduction section of the article references these claims (references 10 - PMID: 17023716 and 11 - PMID: 16291049). A large RCT dated 2007 shows the same results in women. (PMID: 17698683) Directing the user to these references for the claim regarding risk of developing heart disease would be more accurate, although its questionable whether anyone apart from myself would notice! 81.104.186.166 02:38, 7 November 2007 (UTC)
A fellow antioxidant enthusiast! I did my PhD on thiol metabolism, what's your area? PMID: 16291049 is on folate but I'll add (PMID: 17698683) as an additional ref here. Tim Vickers 02:44, 7 November 2007 (UTC)
I'm afraid I'm actually a medical student doing a year of pharmacology. I came across the article whilst studying cardiovascular disease at a greater level of detail (endothelial function, etc).81.104.186.166 02:55, 7 November 2007 (UTC)
Never mind, although medics aren't real doctors, it is quite a good profession! ;) Tim Vickers 02:57, 7 November 2007 (UTC)

[edit] B-carotene question

Under Health Effects - adverse effects: "smokers given beta-carotene supplements", "smokers given beta carotene", and "showed that β-carotene, vitamin A". Which one of these is right (or at least more appropriate)? Fabometric (talk) 14:26, 13 December 2007 (UTC)

Good point, "smokers given supplements containing beta-carotene and vitamin A had increased rates of lung cancer" is more accurate. Thank you. Tim Vickers (talk) 16:02, 13 December 2007 (UTC)

[edit] What's in it for the average reader?

This page is confusing for the average reader. Side by side claims such as "the SU.VI.MAX trial, which suggested that antioxidants have no effect on cause-all mortality", "Antioxidants can cancel out the cell-damaging effects of free radicals,[8] and people who eat fruits and vegetables rich in polyphenols and anthocyanins have a lower risk of cancer, heart disease and some neurological diseases.[119]" and "however antioxidant vitamin supplementation has no detectable effect on the aging process, so the effects of fruit and vegetables may be unrelated to their antioxidant contents.[109][110]" end up meaning nothing for the average reader. People shouldn't have to do a year long literature review and be PhDs in biochemistry to make sense of this article. Can an expert please address the questions everyone has in mind when reading this! Should one take antioxidant supplements? How much? For what? Should one eat foods rich in antioxidants instead? Or is there too much contradicting data to tell? This should be clearly spelled out. I'm a physiology major and the section on health effects confused the hell out of me! How can I possibly evaluate the relevancy of all those studies? What about the average joe who just wants to pick up good eating habits? What is he supposed to think? Come on, we can do better than this! I'm not an expert but I'm sure there are some out there who would have a word to say about this. As it is, it's merely a list of studies that are overall confusing. We need a clear summary and conclusion. Can someone please do some editing and summarizing of this section? We need the average reader to leave this page feeling that s/he understood what the scientific community knows about the health effects antioxidants and what there is doubt and controversy about. Thank you! Horia (talk) 21:24, 14 February 2008 (UTC)

I thought the section in the lead might achieve that "Antioxidants are also widely used as ingredients in dietary supplements in the hope of maintaining health and preventing diseases such as cancer and coronary heart disease. Although some studies have suggested antioxidant supplements have health benefits, other large clinical trials did not detect any benefit for the formulations tested, and excess supplementation may occasionally be harmful." Is this still too confusing and technical? I've also re-written first section of the "disease prevention" section, to try to make this clearer. Tim Vickers (talk) 21:31, 14 February 2008 (UTC)
Seems like a clear summary of current knowledge; 'eat your fruits and veggies and don't waste time with supplements'.CynRNCynRN Talk 18:52, 1 May 2008 (UTC)

[edit] Cancer prevention

The following statement is inaccurate: "people who eat fruits and vegetables, which are good sources of antioxidants, have a lower risk of cancer, heart disease and some neurological diseases.[119]"

It should read: "people who eat fruits and vegetables, which are good sources of antioxidants, have a lower risk of heart disease and some neurological diseases,[119] and there is evidence that some types of vegetables, and fruits in general, probably protect against a number of cancers." (reference: http://www.dietandcancerreport.org/downloads/chapters/chapter_04.pdf - 4.2.7 Conclusions) --Phenylalanine (talk) 23:45, 16 March 2008 (UTC) Y Done

I like that change better than the first quote. --DavidD4scnrt (talk) 05:38, 9 April 2008 (UTC)

[edit] Some General Concerns and Questions - A Possible Clarification

This is a fine overview, and it overall probably deserves its status as a featured star class article. However, there are a couple of suggestions and concerns. First of all, the relationship between antioxidant activity and effects on numerous other cellular pathways is still a bit murky and poorly articulated, both within state-of-the-art science and within the article. The article leaves the reader with the impression that antioxidant compounds have a neatly discreet mechanism of cellular action, when there is plenty of evidence that this is simply not true, and indeed could not be true.

For example, it is clear that numerous classical polyphenol antioxidants have a host of other effects on cellular mechanisms beyond reduction of reactive oxygen species, including what appears to be a common down-regulation of nuclear factor kappa B (a transcription factor widely regarded as a fundamental link between chronic inflammation and the eventual generation of cancer). It may turn out that numerous phytochemicals protect us from cancer not primarily because of reduction of reactive oxygen species and associated damage to DNA but also because of their inhibitory effects on NF kappa B, and their associated promotion of apoptosis in damaged cells. Additionally, the classic polyphenol antioxidant resveratrol (one of the hottest molecules in the anti-aging business) may have its most biologically protective effects mediated through mechanisms that have little or nothing to do with the reduction of oxidative stress. For example, resveratrol appears to activate surtuins, and about 20 other cellular pathways (including COX-2, iNOS, JNK, MEK, AP-1, p53, Bax, caspases, survivin, cyclins, Bcl-2, CIAP, Egr-1, PKC, PKD, casein kinase II, 5-LOX, VEGF, IL-1, IL-6, IL-8, just to name a partial list). (see Aggarwal 2006 in Biochemical Pharmacology for an excellent review).

Indeed after reading some of the recent molecular work on antioxidant phytochemicals, one has to genuinely wonder if the term antioxidant really does them justice. It seems like they are more very complex cellular physiology modulators affecting transcription pathways, energy metabolism pathways, inflammatory pathways, apoptotic mechanisms, and a dizzying array of cellular signaling processes. However the term "cell physiology modulators" obviously is not going to catch on or replace the term "antioxidants". However, if this is truly a star class article in Wikipedia, it should reflect some of these considerations. DFW April 8, 2008

Hi there, thanks for the comments. The problem is that this article is about "antioxidants" and the antioxidant activities of various enzymes and compounds, the fact that some compounds may have other activities in addition to their antioxidant effects is something that should be discussed in the articles on these particular compounds but wouldn't really fit in the article about their antioxidant effects. For example, I could write a lot about the role of glutathione in xenobiotic metabolism, but this wouldn't belong in this article. However, you are right that I should probably note that the polyphenolics in particular have other effects in the section on clinical trials, since this may be one reason why the level of antioxidant intake don't seem to correlate with any health benefits. Tim Vickers (talk) 00:16, 9 April 2008 (UTC)

Hi Tim

Thanks for the response. I do think that people assume that plant compounds labeled as antioxidants (especially flavonoids/polyphenols) are good for us simply because they reduce oxidative stress. I guess my basic point is just that like a lot of popular and trendy ideas, the notion that the reduction of oxidative stress is the primary benefit associated with these "antioxidants" may be a major oversimplification. I do think this is why classic antioxidants such as vitamin E have been frankly a major bust (in relationship to all the major diseases of aging such as heart disease, cancer, and Alzheimer's disease) whereas these more complex polyphenol compounds do not look like a bust at all. I also think that the emerging evidence favors the hypothesis that up regulation of endogenous antioxidant systems (particularly glutathione) may be more protective than pouring a lot of exogenous antioxidants into the system, but perhaps it is too early to say. But I appreciate your feedback and as I said overall it's a fine effort.

Doug Watt, Harvard Medical School

[edit] JAMA citation

These harmful effects may also be seen in non-smokers, as a recent meta-analysis including data from approximately 180,000 patients showed that β-carotene, vitamin A or vitamin E supplementation is associated with increased mortality.[132] However, this meta-analysis found no significant effect from vitamin C supplementation on mortality.

This sites the JAMA study, which has been criticized ( http://oregonstate.edu/dept/ncs/newsarch/2007/Feb07/vitaminstudy.html ) for methodological problems and a study selection bias. The statement should probably be softened to reflect this criticism (both from LPI and others). This is doubly true given how recently that particular report was published. --Nachtrabe 21:40, 20 March 2007 (UTC)

This criticism has not been published in a peer-reviewed journal, so I think it carries comparatively little weight. If there are indeed serious methodological problems of this paper then when the journal publishes corrections or commentary papers they should certainly be added to the article. However, criticisms that appear to have been published on the researcher's university news website do not really pass the quality guidelines. TimVickers 00:50, 21 March 2007 (UTC)
Given that the paper in question was published three weeks ago, making authoritative statements from it when there are potential methodological problems is a bit overzealous. Research is an ongoing process, and IMHO the study should be considered valid only after there has been some time for the peer review process to go into effect. This is particularly true when so many doubts have been raised by different groups. From NPI Center: International Experts Dispute Conclusions Of Antioxidant Review, Meta-Analysis On Antioxidants Provides Muddled Conclusions. --Nachtrabe 19:31, 21 March 2007 (UTC)
Peer-review occurs before papers are published and I do not find it surprising that the "International Alliance of Dietary Supplement-Food Associations" is critical of a study suggesting many of their products are harmful. This review is a serious study published in a top-quality journal, it's conclusions deserve to be highlighted in this article. Moreover, it is not like this is a result out of line with other recent studies. The last major meta-analysis previous to this one (Link) that looked at people with colon cancer also saw an increase in mortality. TimVickers 19:48, 21 March 2007 (UTC)

Here's some criticism of the flawed study, including a lot references: Another Flawed Attack Against Antioxidants Regulations 18:01, 23 March 2007 (UTC) The average age of the subjects was 62! You have to use antioxidants before the damage is done. Preventing damage is easier than reversing it. Regulations 18:06, 23 March 2007 (UTC)

This is not a peer-reviewed study, so it can't be given as much weight as higher quality publications. See the quality guidelines. TimVickers 18:27, 23 March 2007 (UTC)
It's not a study at all. I'm not asking that that article be cited. I am saying that it has a lot of references in it that can be used in this article. It's got links to scientists saying that the study was flawed. Their opinions are noteworthy on whether a study is flawed or not. You don't need a "peer-reviewed study" claiming that experiment is flawed. But more importantly, the article is chocked full of complete citation references to studies that can be cited in this article that prove the benefit of antioxidants. Regulations 18:47, 23 March 2007 (UTC)

I don't think we should be trying to "prove" anything in this article, that is completely the wrong approach. What we should try to do is lay out as clearly as possible the data on the health effects of antioxidants. I would be very happy for you to expand the section on "Disease prevention" with high-quality peer-reviewed articles. TimVickers 18:53, 23 March 2007 (UTC)

Read closer. I didn't say cite studies "to prove." I said cite the studies "that prove." Regulations 18:57, 23 March 2007 (UTC)

The authors of the Feb 2007 JAMA article have updated and extended the meta-analysis in a review published by The Cochrane Collaboration on April 15, 2008. Subsequent to the JAMA article there were Letters to the Editor published in July 2007. Several of these pointed out errors in the original meta-analysis, and some of the criticisms were addressed in the Cochrane review. The authors present but do not stress that the greatest mortality increases were seen in the A, E and BC studies using the highest doses - in some instances higher than what the DRIs set as safe upper limits. The Cochrane review does include the big studies with smokers (including ATBC and CARET), and as these showed increased mortality for beta-carotene, the compiled results may be skewed. David notMD (talk) 17:30, 16 April 2008 (UTC)

Thanks, I've added a citation, but can only read the abstract until the article is published. Tim Vickers (talk) 18:35, 16 April 2008 (UTC)
A pdf of the full Cochrane review can be found here: http://www3.interscience.wiley.com/homepages/106568753/CD007176.pdf. The critical Letters to the Editor David notMD mentions are found in JAMA, Vol. 298 No. 4, July 25, 2007. It should be noted that in a reply in JAMA, published by the authors behind the meta-analysis, the following is written in response to criticism that the results are skewed by two large beta-carotene trials on smokers:

"Taylor and Dawsey argue that the inclusion of 2 lowbias risk trials on beta carotene in smokers may drive our results. However, additional analysis show that antioxidants have no significant effect on mortality irrespective of whether these 2 trials were included (RR, 1.02; 95% CI, 0.98-1.06) or not included (RR, 1.00; 95% CI, 0.97-1.04). Our analysis had included a total of 25 beta carotene trials. Because we have no individual patient data, we are unable to analyze the effect of beta carotene in smokers separately. In response to Taylor and Dawsey, we have conducted post hoc analysis that exclude the 25 trials on beta carotene. When these trials were excluded, the subgroup analysis found no significant effect of vitamin A (RR, 1.23; 95% CI, 0.91- 1.66) or vitamin E (RR, 1.00; 95% CI, 0.94-1.06) when all trials were included irrespective of bias risk or when only trials with a low risk of bias were included (RR, 1.21; 95% CI, 0.88-1.67; RR, 1.04; 95% CI, 0.97-1.12, respectively)."

In essence, when the group of studies containing the beta-carotene trials is excluded, no significant effect on mortality is found for either vitamin A or E.
Quote from the Cochrane review about doses:

"Most trials investigated the effects of supplements administered at higher doses than those commonly found in a balanced diet, and some of the trials used doses well above the recommended daily allowances and even above the tolerable upper intake levels (Anonymous 2000a; Anonymous 2000b) (see Table 08 for overview of recommended dietary allowance, tolerable upper intake level, and experimental doses and regimen used). Our meta-regression analysis revealed significant effects of dose of beta-carotene, vitamin A, and selenium on mortality."

In the light of these peer-review references and other criticisms, I would find it reasonable to edit the section mentioning the meta-analysis to put the matter of adverse effects in context with dosage and the uncertainties connected with estimating causality on the basis of a study of this type. (JTrier (talk) 14:45, 17 April 2008 (UTC))
Go ahead, although I hope the article already makes it clear that randomised controlled trials are much better at testing a causal relationship than the earlier observational studies that can only show an association. Tim Vickers (talk) 16:54, 17 April 2008 (UTC)