title: Beta-carotene metabolites enhance inflammation-induced oxidative DNA damage in lung epithelial cells.
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.
authors.affiliation: Department of Health Risk Analysis and Toxicology, Research Institute NUTRIM, Maastricht University, 6200MD Maastricht, The Netherlands.
authors.forename: Yvonne G J
authors.initials: YG
authors.lastname: van Helden
authors.forename: Jaap
authors.initials: J
authors.lastname: Keijer
authors.forename: Ad M
authors.initials: AM
authors.lastname: Knaapen
authors.forename: Sandra G
authors.initials: SG
authors.lastname: Heil
authors.forename: Jacob J
authors.initials: JJ
authors.lastname: Briedé
authors.forename: Frederik J
authors.initials: FJ
authors.lastname: van Schooten
authors.forename: Roger W L
authors.initials: RW
authors.lastname: Godschalk
mesh_terms: D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D004249:DNA Damage / Q000187:drug effects*; D004578:Electron Spin Resonance Spectroscopy; D004847:Epithelial Cells / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D007249:Inflammation; D018836:Inflammation Mediators / Q000494:pharmacology*; D008168:Lung / Q000378:metabolism / Q000473:pathology; D009152:Mutagenicity Tests; D018375:Neutrophil Activation / Q000187:drug effects; D009504:Neutrophils / Q000201:enzymology* / Q000473:pathology; D010084:Oxidation-Reduction / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D009195:Peroxidase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011687:Purines / Q000032:analysis; D014212:Tretinoin / Q000494:pharmacology; D014801:Vitamin A / Q000494:pharmacology; D019207:beta Carotene / Q000494:pharmacology*
chemical_list: D018836:Inflammation Mediators; D011687:Purines; D019207:beta Carotene; D014801:Vitamin A; D014212:Tretinoin; D006861:Hydrogen Peroxide; D009195:Peroxidase