Derek Lowe's commentary on drug discovery and the pharma industry. An editorially independent blog from the publishers of Science Translational Medicine . All content is Derek’s own, and he does not in any way speak for his employer.

I’ve highlighted several articles here over the years that cast doubt (to say the least) on the popular belief that Antioxidants Are Always Good For You. These other views do not seem to have penetrated the public consciousness yet, though, to judge by the way that foods and supplements are advertised. Today brings another example, and it vividly illustrates how the simple story gets things very wrong.

You would imagine that if any tissue is going to be susceptible to oxidative damage, it would be the lungs (where all that oxygen is absorbed in the first place). And indeed, such damage is seen as a component of many lung diseases, from COPD to various cancers. The antioxidant N-acetylcysteine has been widely used as a supplement in general (here in the US, you can find piles of it in the appropriate aisles of drug stores and vitamin/supplement stores), and it’s been particularly recommended for lung disease, both for its antioxidant effects and its ability to thin out mucus production.

Now, there are already data to suggest that that’s a problem. In mice with activating mutations in K-Ras or B-Raf, which are commonly seen in human lung cancers, antioxidants (NAC and vitamin E) actually seem to accelerate the growth of the tumors. That was reported in 2014, and you won’t hear much about it down at the drug store. Now there’s a study looking at not just growth of existing tumors, but tumor initiation itself, and the news is disturbingly similar. But it’s even more important to realize that (up to a point) NAC supplementation looks like it’s doing a lot of good.

This paper, from a multicenter French team, looked at three populations of aging mice: normal controls (+/+ for JunD), others that had had the JunD gene knocked out (-/-), and heterozygotes (+/-) who had reduced expression of the protein. JunD is recognized to regulate a whole suite of antioxidant responses in cells – Nrf2 is another example of this, and both of those have been found to be deficient (at both the mRNA and protein level) in the lung tissue of human patients with COPD.

Both the normal mice and the JunD-deficient ones got either NAC-laced water along with their mouse chow, or just water+vehicle as a control: a perfectly reasonable experimental design to assess the effects of aging, JunD levels, and NAC supplementation across each combination of these. And as each cohort aged, there were several interesting changes (which have been noted in some other studies as well). For example, JunD was upregulated with age in the mice who still had the gene, and its down stream oxidative-stress proteins (such as superoxide dismutase, Hmox, and others) increased as well (although not in the -/- animals, as you might have figured). Consistent with an earlier study from this same group, loss of JunD exacerbated oxidative stress in the lungs as the animals aged, as well.

Here’s the good part: the animals who got NAC supplementation really did show significantly fewer of those signs of oxidative damage in their lung tissue. It also reduced signs of cell senescence and overt histological damage of aging as well, such as emphysema lesions (all of these were markedly worse in the JunD knockouts, but NAC improved them as well). So far, so good, and this is exactly the case you’d make if you were pitching NAC as something people should take for healthy lungs as they age. But hold on.

None of the aged normal mice showed signs of adenocarcinoma developing in their lung tissue. But 10% of the aged normals getting NAC supplementation showed it. None of the aged JudD knockouts showed any, either, but 50% of the aged JunD knockouts getting the NAC supplementation had it. The best guess is that cell senescence pathway that seemed to be inhibited with the NAC: some of these are in fact cells that should have died and didn’t, and went on to become cancerous: