Tag Archives: ATBC trial

Why antioxidants may be bad for you

Antioxidants (vitamin E, beta carotene, vitamin C etc. etc. ) were very big a while ago. They were held to prevent all sorts of bad things (heart attack, stroke). However one pretty good study done years and years ago (see the bottom) showed that they increased the risk of lung cancer in 29,000 Finnish male smokers by 18%. People still take them however.

Now we are beginning to find out the good things that oxidation does for you. One oxidation product is 8-oxo-guanine–https://en.wikipedia.org/wiki/8-Oxoguanine — and it is estimated that it occurs 100,000 time a day in every cell in our body. This isn’t very often as we have .24 x 3,200,000 = 768,000,000 guanines in our genome.

One good thing 8-oxo-guanine may do for you is turn on gene transcription [ Proc. Natl. Acad. Sci. vol. 114 pp. 2788 – 2790, 2604 – 2609 ’17 ].This occurs when the guanine occurs in an elegant DNA structure called a G-quartet (G quadruplex) — https://en.wikipedia.org/wiki/G-quadruplex. Oxidation recruits an enzyme to remove it (8-oxo-guanine glycosylase — aka OGG1 ) generating a DNA lesion — a sugar in the backbone without a nucleotide attach. This causes the binding of Apurinic/Apyrmidic Endonuclease 1 (APE1) which recruits other things to repair the DNA.

As you know DNA in our cells is compacted 100,000 fold to fit its 1 meter length into a nucleus .00001 meters in size. Compaction involves wrapping the helix around all nucleosomes and then binding the nucleosomes together.

It’s pretty hard for RNA polymerase to even get to a gene to transcribe it into mRNA, and DNA lesions cause opening up of this compaction so repair enzymes can actually get to the double helix.

One such gene is Vascular Endothelial Growth Factor (VEGF), a gene induced by low oxygen (hypoxia). The promoter of VEGF has a potential G quadruplex sequence. If the authors put 8-oxo-guanine at 5 different positions in the G quartet, transcription of the VEGF gene was increased 2 – 3 times over the next few days. Showing the importance of the DNA lesion, if OGG1 levels were decreased this didn’t happen — showing that guanine oxidation and with the subsequent formation of a DNA lesion is required for increased transcription of VEGF.

Aside from being another mechanism for gene activation under oxidative stress, 8-oxo-guanine may actually be another epigenetic DNA modification, like 5 methyl cytosine.

So this may explain the result immediately below.

[ New England J. Med. vol. 330 pp. 1029 – 1035 ’94 ] The Alpha-Tocopherol, Beta-Carotene Trial (ATBC trial) randomized double blind placebo controlled of daily supplementation with alpha-tocopherol (a form of vitamin E), beta carotene or both to see if it reduced the incidence of lung cancer was done in 29,000 Finnish male smokers ages 50 – 69 (when most of the damage had been done). They received either alpha tocopherol 50 mg/day, beta carotene 20 mg/day or both. There was a high incidence of lung cancer (876/29000) during the 5 – 8 year period of followup. Alpha tocopherol didn’t decrease the incidence of lung cancer, and there was a higher incidence among the men receiving beta carotene (by 18%). Alpha tocopherol had no benefit on mortality (although there were more deaths from hemorrhagic stroke among the men receiving the supplement). Total mortality was 8% higher among the participants on beta carotene (more deaths from lung cancer and ischemic heart disease). It is unlikely that the dose was too low, since it was much higher than the estimated intake thought to be protective in the uncontrolled dietaryt studies. The trial organizers were so baffled by the results that they even wondered whether the beta-carotene pills used in the study had become contaminated with some known carcinogen during the manufacturing process. However, tests have ruled out that possibility.

Needless to say investigators in other beta carotene clinical trials (the Women’s Health Study, the Carotene and Retinoid Efficacy Trial) are upset. [ Science vol. 264 pp. 501 – 502 ’94 ] “In our heart of hearts, we don’t believe [ beta carotene is ] toxic” says one researcher. Touching isn’t it. Such faith in a secular age, particularly where other people’s lives are at stake. I love it when ecology, natural vitamins and pseudoscience take it in the ear.

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