Beta-carotene metabolites enhance inflammation-induced oxidative DNA damage in lung epithelial cells

Our plain-English summary of Beta-carotene metabolites enhance inflammation-induced oxidative DNA damage in lung epithelial cells, by Y.G. van Helden, J. Keijer, A.M. Knaapen, et al (Free Radical Biology & Medicine, 2009).

The study

• Authors: Y.G. van Helden, J. Keijer, A.M. Knaapen, S.G. Heil, J.J. Briedé, F.J. van Schooten, R.W. Godschalk
• Journal: Free Radical Biology & Medicine
• Published: 2009;46(2):299-304
• Cited by: 35 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

beta-Carotene (BC) intake has been shown to enhance lung cancer risk in smokers and asbestos-exposed subjects (according to the ATBC and CARET studies), but the mechanism behind this procarcinogenic effect of BC is unclear. Both smoking and asbestos exposure induce an influx of inflammatory neutrophils into the airways, which results in an increased production of reactive oxygen species and formation of promutagenic DNA lesions. Therefore, the aim of our study was to investigate the effects of BC and its metabolites (BCM) on neutrophil-induced genotoxicity. We observed that the BCM vitamin A (Vit A) and retinoic acid (RA) inhibited the H(2)O(2)-utilizing enzyme myeloperoxidase (MPO), which is released by neutrophils, thereby reducing H(2)O(2) conversion. Moreover, BC and BCM were able to increase (.)OH formation from H(2)O(2) in the Fenton reaction (determined by electron spin resonance spectroscopy). Addition of Vit A and RA to lung epithelial cells that were co-incubated with activated neutrophils resulted in a significant increase in the level of oxidized purines assessed by the formamidopyrimidine DNA glycosylase-modified comet assay. These data indicate that BCM can enhance neutrophil-induced genotoxicity by inhibition of MPO in combination with subsequent increased formation of hydroxyl radicals.

In plain English

This laboratory study did not examine asbestos or people exposed to it. The authors set out to explore why beta-carotene supplements were linked with more lung cancer in smokers and asbestos-exposed people in two earlier trials, ATBC and CARET. They tested beta-carotene, three of its breakdown products (vitamin A, retinoic acid and retinal), and vitamin E. The test system was human lung cancer cells (A549) grown together with activated white blood cells (neutrophils) taken from six healthy nonsmoking donors. Vitamin A and retinoic acid reduced the activity of the neutrophil enzyme myeloperoxidase by 31% and 21%, respectively; beta-carotene, retinal and vitamin E did not. In a chemical test, beta-carotene, its breakdown products and vitamin E all increased formation of hydroxyl radicals by about 40%. With vitamin A and retinoic acid, oxidative DNA damage in the lung cells rose four- and threefold, respectively. The other substances caused no significant increase. The authors concluded that these breakdown products have a role in neutrophil-induced DNA damage. They said further research is needed to verify whether these effects matter in the lung of a living organism.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory (in vitro) experiments on cultured human lung epithelial cells, isolated human neutrophils and cell-free chemical systems
• Who was studied: A549 human lung carcinoma epithelial cells, co-cultured with neutrophils from the blood of six healthy nonsmoking human donors (two females, four males, aged 25 to 50 years); no asbestos-exposed people were studied
• Exposure: Beta-carotene (5 μM), the beta-carotene metabolites retinoic acid, retinal and vitamin A (10 μM each), and vitamin E (40 μM), with concentrations based on serum levels seen in the ATBC and CARET trials. Asbestos itself was not tested.
• Main results:
  • In the iron and hydrogen peroxide (Fenton) chemical system, beta-carotene, its metabolites and vitamin E increased hydroxyl radical formation by approximately 40% (p less than 0.001)
  • In the superoxide-generating system, the same amounts of radical signal were formed with beta-carotene, its metabolites and vitamin E as with the control
  • In the neutrophils from six donors, vitamin A and retinoic acid inhibited myeloperoxidase activity by 31% and 21%, respectively, in a dose-dependent way. Beta-carotene, retinal and vitamin E did not affect it.
  • Catalase activity was not affected by any of the vitamins tested
  • In lung epithelial cells co-cultured with activated neutrophils, vitamin A and retinoic acid produced a four- and threefold increase in oxidative DNA damage, respectively. Beta-carotene, retinal and vitamin E caused no significant increase.
  • The ability of the vitamins to increase DNA damage correlated with their ability to inhibit myeloperoxidase (r = −0.82, p less than 0.05)
• The authors' conclusion: The authors concluded that beta-carotene metabolites have a role in neutrophil-induced DNA damage. In their view, vitamin A and retinoic acid lowered myeloperoxidase activity and increased hydroxyl radical formation, which led to more oxidized DNA in the lung cells. They said the relevance of this for the lung in vivo still needs to be verified.
• Limitations the authors state:
  • Hydrogen peroxide, which the authors consider central to the proposed mechanism, was not measured, because available methods are affected by beta-carotene
  • The highest retinoic acid concentration used may be higher than levels normally found in the body
  • Some epidemiological studies of a myeloperoxidase gene variant appear to conflict with the authors' hypothesis
  • The findings come from cell experiments; their relevance in the lung in vivo has not been verified

Topics

Medical terms in this study, explained in our Lexicon: Inflammation, Lung Cancer, Asbestos Exposure, Reactive Oxygen Species (ROS), DNA lesions, Genotoxicity, Fenton Reaction, Comet Assay.

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