Adaptation to acrolein through upregulating the protection by glutathione in human bronchial epithelial cells: The materialization of the hormesis concept

[Display omitted] •GSH and acrolein react in a stoichiometry of 1:1.•Intracellular GSH forms the first line of defense against acrolein-induced toxicity.•Acrolein induces adaptation by increasing GSH synthesis.•Toxicity of acrolein can be alleviated by small hormetic dosages.•Hormesis does affect xenobiotic toxicity. 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 (⩾10μM) 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 (3μM), 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.