title: Adaptation to acrolein through upregulating the protection by glutathione in human bronchial epithelial cells: the materialization of the hormesis concept.
abstract: Acrolein is a thiol reactive compound present in cigarette smoke and plays a pivotal role in the deleterious effects of smoking. Acrolein causes toxicity in human bronchial epithelial cells in a dose dependent manner. GSH forms the first line of defense against acrolein-induced toxicity. At high doses of acrolein (⩾10 μM) the capacity of the cellular protection by GSH is overwhelmed and GSH is not able to quench all the acrolein, resulting in cytotoxicity. At a relatively low dose of acrolein (3 μM), no cytotoxicity is observed due to protection by GSH. Moreover we found that exposure to a low dose of acrolein protects cells against the toxic effect of a second higher dose of acrolein. The adaptation to acrolein is induced via Nrf2 mediated gene expression of γ-glutamylcysteine synthetase leading to elevated GSH levels. This upregulation of the protection by GSH demonstrates a hormetic response to acrolein. Hormesis is an adaptive or compensatory response induced by a relatively subtle challenge of homeostasis by a toxic compound. Insight into the mechanism of hormesis is mandatory for a more accurate societal regulation of toxic compounds.
authors.affiliation: Department of Toxicology, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, The Netherlands. Electronic address: mireille.sthijns@maastrichtuniversity.nl.
authors.forename: Mireille M J P E
authors.initials: MM
authors.lastname: Sthijns
authors.affiliation: Department of Toxicology, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, The Netherlands; Department of Pathology, College of Medicine, University of Vermont, Burlington, VT, USA.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Randall
authors.affiliation: Department of Toxicology, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, The Netherlands.
authors.forename: Aalt
authors.initials: A
authors.lastname: Bast
authors.affiliation: Department of Toxicology, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, The Netherlands. Electronic address: g.haenen@maastrichtuniversity.nl.
authors.forename: Guido R M M
authors.initials: GR
authors.lastname: Haenen
mesh_terms: D000171:Acrolein / Q000009:adverse effects*; D001980:Bronchi / Q000166:cytology / Q000187:drug effects*; D002460:Cell Line; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D005721:Glutamate-Cysteine Ligase / Q000235:genetics; D005978:Glutathione / Q000235:genetics / Q000378:metabolism*; D059165:Hormesis / Q000187:drug effects; D006801:Humans; D008958:Models, Molecular; D015854:Up-Regulation / Q000187:drug effects*
chemical_list: D000171:Acrolein; D005721:Glutamate-Cysteine Ligase; D005978:Glutathione
keywords: Acrolein; GSH; Hormesis; Human bronchial epithelial cells; γGCS