Polyphenol cytotoxicity induced by the bacterial toxin pyocyanin: role of NQO1

Pyocyanin is an important bacterial redox-active toxin produced by the opportunistic human pathogen Pseudomonas aeruginosa. The bacterium is a cause of serious infections of the respiratory tract, particularly for those with cystic fibrosis and for those with burn injuries. Pyocyanin induces oxidative stress and causes cells to become prematurely senescent, which compromises tissue remodeling and wound repair. A diverse range of antioxidants have been found useful in preventing oxidant-induced cellular senescence, including quercetin, a common dietary polyphenol. This study evaluated the effectiveness of three common polyphenols (quercetin, (+)-catechin, and (-)-epicatechin) as potential inhibitors of pyocyanin-induced senescence. Whereas at the lowest concentration the polyphenols maintained cellular replicative capacity, in the presence of pyocyanin they unexpectedly displayed concentration-dependent cytotoxicity with a rank order of quercetin>epicatechin>>catechin. On oxidation, polyphenols with B-ring catechol functionality form toxic alkylating quinones that are normally inactivated by cellular antioxidant defense and redox maintenance systems, including reduction by ascorbate and NAD(P)H:quinone oxidoreductase 1 (NQO1). Pyocyanin inhibited cellular NQO1 activity at low micromolar concentrations, but the presence of exogenous ascorbate eliminated pyocyanin-induced polyphenol cytotoxicity. These data indicate that pyocyanin compromises cellular redox maintenance systems, leaving cells susceptible to the adverse effects of otherwise nontoxic redox-active compounds.