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


METHODS
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.


RESULTS
Autoxidation of Fe(2+)in vitro increased in the presence of SIH or HAPI (but not BIH), an effect partially blocked by Fe(2+) 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. Fe(2+) 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.


CONCLUSIONS
SIH iron chelators display both prooxidant (increasing the autoxidation rate of Fe(2+)) and antioxidant (activating Nrf2 signaling) effects.


CONCLUSIONS
Activation by SIH iron chelators of a hormetic antioxidant response contributes to their antioxidant properties and modulates the anti- and pro-oxidant balance.
Chemistry Department, Hendrix College, Conway, AR 72032, USA. Electronic address: caro@hendrix.edu.
Andres A
AA
Caro
Chemistry Department, Hendrix College, Conway, AR 72032, USA.
Ava
A
Commissariat
Chemistry Department, Hendrix College, Conway, AR 72032, USA.
Caroline
C
Dunn
Chemistry Department, Hendrix College, Conway, AR 72032, USA.
Hyunjoo
H
Kim
Chemistry Department, Hendrix College, Conway, AR 72032, USA.
Salvador Lorente
SL
García
Chemistry Department, Hendrix College, Conway, AR 72032, USA.
Allen
A
Smith
Chemistry Department, Hendrix College, Conway, AR 72032, USA.
Harrison
H
Strang
Chemistry Department, Hendrix College, Conway, AR 72032, USA.
Jake
J
Stuppy
Chemistry Department, Hendrix College, Conway, AR 72032, USA.
Linda P
LP
Desrochers
Chemistry Department, Hendrix College, Conway, AR 72032, USA.
Thomas E
TE
Goodwin
D000447:Aldehydes / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology*; D005978:Glutathione / Q000378:metabolism; D056945:Hep G2 Cells; D006801:Humans; D006835:Hydrazones / Q000494:pharmacology*; D007502:Iron Chelating Agents / Q000494:pharmacology*; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D010084:Oxidation-Reduction; D017382:Reactive Oxygen Species / Q000378:metabolism
D000447:Aldehydes; D000975:Antioxidants; D006835:Hydrazones; D007502:Iron Chelating Agents; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D017382:Reactive Oxygen Species; C413684:salicylaldehyde isonicotinoyl hydrazone; D005978:Glutathione
Antioxidant; Glutathione; Iron; Nrf2; Oxidative stress; Salicylaldehyde isonicotinoyl hydrazone