Prooxidant and antioxidant properties of salicylaldehyde isonicotinoyl hydrazone iron chelators in HepG2 cells

• Published in: Biochimica et biophysica acta Vol. 1850; no. 11; pp. 2256 - 2264
• Main Authors: Caro, Andres A., Commissariat, Ava, Dunn, Caroline, Kim, Hyunjoo, García, Salvador Lorente, Smith, Allen, Strang, Harrison, Stuppy, Jake, Desrochers, Linda P., Goodwin, Thomas E.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.11.2015
• Subjects: Aldehydes - pharmacology; Antioxidant; Antioxidants - pharmacology; Glutathione; Glutathione - metabolism; Hep G2 Cells; Humans; Hydrazones - pharmacology; Iron; Iron Chelating Agents - pharmacology; NF-E2-Related Factor 2 - metabolism; Nrf2; Oxidation-Reduction; Oxidative stress; Reactive Oxygen Species - metabolism; Salicylaldehyde isonicotinoyl hydrazone; BIH; Oxidative stress; DIP; Iron; Antioxidant; PG SK-DA; DCFH-DA; Gcl; Gclc; LIP; HAPI; SIH; MEM; Salicylaldehyde isonicotinoyl hydrazone; Nrf2; ROS; Glutathione
• ISSN: 0304-4165; 0006-3002; 1872-8006
• DOI: 10.1016/j.bbagen.2015.08.005

Salicylaldehyde isonicotinoyl hydrazone (SIH) is an iron chelator of the aroylhydrazone class that displays antioxidant or prooxidant effects in different mammalian cell lines. Because the liver is the major site of iron storage, elucidating the effect of SIH on hepatic oxidative metabolism is critical for designing effective hepatic antioxidant therapies. Hepatocyte-like HepG2 cells were exposed to SIH or to analogs showing greater stability, such as N′-[1-(2-Hydroxyphenyl)ethyliden]isonicotinoyl hydrazide (HAPI), or devoid of iron chelating properties, such as benzaldehyde isonicotinoyl hydrazone (BIH), and toxicity, oxidative stress and antioxidant (glutathione) metabolism were evaluated. Autoxidation of Fe2+in vitro increased in the presence of SIH or HAPI (but not BIH), an effect partially blocked by Fe2+ chelation. Incubation of HepG2 cells with SIH or HAPI (but not BIH) was non-toxic and increased reactive oxygen species (ROS) levels, activated the transcription factor Nrf2, induced the catalytic subunit of γ-glutamate cysteine ligase (Gclc), and increased glutathione concentration. Fe2+ chelation decreased ROS and inhibited Nrf2 activation, and Nrf2 knock-down inhibited the induction of Gclc in the presence of HAPI. Inhibition of γ-glutamate cysteine ligase enzymatic activity inhibited the increase in glutathione caused by HAPI, and increased oxidative stress. SIH iron chelators display both prooxidant (increasing the autoxidation rate of Fe2+) and antioxidant (activating Nrf2 signaling) effects. Activation by SIH iron chelators of a hormetic antioxidant response contributes to their antioxidant properties and modulates the anti- and pro-oxidant balance. •SIH increased ferrous iron autoxidation and ROS generation in HepG2 cells.•SIH increased total glutathione and induced GCLC in HepG2 cells.•GCLC induction by SIH in HepG2 cells depended on Nrf2 activation.•Activation by SIH of antioxidant signaling contributes to its antioxidant properties.•SIH modulates the anti-/pro-oxidant balance by both anti- and pro-oxidant effects.