Nicotine Mediates Hypochlorous Acid-Induced Nuclear Protein Damage in Mammalian Cells

Abstract

Activated neutrophils secrete hypochlorous acid (HOCl) into the extracellular space of inflamed tissues. Because of short diffusion distance in biological fluids, HOCl damaging effect is restricted to the extracellular compartment. The current study aimed at investigating the ability of nicotine, a component of tobacco and electronic cigarettes, to mediate HOCl-induced intracellular damage. We report, for the first time, that HOCl reacts with nicotine to produce nicotine chloramine (Nic-Cl). Nic-Cl caused dose-dependent damage to proliferating cell nuclear antigen (PCNA), a nuclear protein, in cultured mammalian lung and kidney cells. Vitamin C, Trolox, glutathione, and N-acetyl-L-cysteine inhibited the Nic-Cl-induced PCNA damage, implicating oxidation in PCNA damage. These findings point out the ability of nicotine to mediate HOCl-induced intracellular damage and suggest antioxidants as protective measures. The results also raise the possibility that Nic-Cl can be created in the inflamed tissues of tobacco and electronic cigarette smokers and may contribute to smoking-related diseases.

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“…A plausible explanation for ROS generation is the observed infiltration of inflammatory cells and associated increase of NOX-1 activity which generates a surplus of superoxide anions [44]. Additionally, the increased MPO levels trigger overshooting of hypochlorous acid, a robust cytotoxic oxidant [39, 45]. The current findings also revealed an upregulation of Nrf-2 and HO-1 upstream signals, probably as compensatory mechanisms to counteract ROS generation.…”

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