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Nitric oxide, chronic iron and copper overloads and regulation of redox homeostasis in rat liver

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Abstract

Iron [Fe(II)] and copper [Cu(II)] ions produced liver oxidative stress and damage, and as a consequence, changes in the antioxidant protection. The objective of this work is to evaluate whether control of redox homeostasis in chronic overload of Fe(II) and Cu(II) is associated with nitric oxide (NO) and antioxidant enzymes protection in liver. Male Sprague–Dawley rats of 80–90 g received the standard diet ad libitum and drinking water supplemented with either 1.0 g/L of ferrous chloride (0.1% w/v, n = 24) or 0.5 g/L cupric sulfate (0.05% w/v, n = 24) for 42 days. The activities of the enzymes involved in the control of cellular redox homeostasis, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, superoxide dismutase (SOD), catalase and glutathione peroxidase (GPx), were determined by spectrophotometric methods, and NO production was determined by the determination of nitrite levels in liver. Chronic overload with Fe(II) and Cu(II) led to a significant increase of NO production while hampering the activity of NADPH oxidase. Meanwhile, the animals supplemented with Fe(II) showed a decrease in SOD and Gpx activities in liver homogenates with respect to baseline activity after 7 days of treatment, whereas the rats which received Cu(II) showed an increased SOD and catalase activity after 28 and 7 days of chronic overload. Further research is required to understand whether the modulation of the activity of these enzymes upon Cu and Fe overload is involved in a common toxic pathway or may serve to control the steady state of oxidant species related to redox signaling pathways.

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Abbreviations

AMP:

5′-Adenosine monophosphate

AMPK:

AMP-activated protein kinase

ATOX1:

Antioxidant chaperone for copper 1

C50 :

Metal content necessary to produce the half of the maximal effect

c-GMP:

Cyclic guanosine monophosphate

CSS:

Copper chaperone for superoxide dismutase

eNOS:

Endothelial nitric oxide synthase

GPx:

Glutathione peroxidase

GSH:

Glutathione

GSSG:

Oxidized glutathione

H2O2 :

Hydrogen peroxide

HO· :

Hydroxyl radical

iNOS:

Inducible nitric oxide synthase

NADPH:

Nicotinamide adenine dinucleotide phosphate oxidase

nNOS:

Neuronal nitric oxide synthase

NO:

Nitric oxide

O2 :

Oxygen

O2 − :

Superoxide anion

1O2 :

Singlet oxygen

ROOH:

Organic hydroperoxides

ROO. :

Hydroperoxyl radical

SOD:

Superoxide dismutase

SOD1:

Cu,Zn-SOD (cytosolic SOD)

SOD2:

Mn-SOD (mitochondrial SOD)

t 1/2 :

Time necessary to produce the half of the maximal effect

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Acknowledgements

Authors thank Professor Alberto Boveris for his teachings and scientific contributions at the beginning of this research work, guiding the development of this experimental line. This study was supported by grants from the University of Buenos Aires (UBACyT 20020170100197BA); the National Research Council of Argentina (CONICET) and the National Agency of Science and Technology of Argentina (ANPCYT) (PICT-2016-002077).

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Authors and Affiliations

  1. Departamento de Ciencias Químicas, Cátedra de Química General e Inorgánica, Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Junin 956, 1113AAD, Buenos Aires, Argentina

    Fabiana Lairion, Christian Saporito-Magriñá, Rosario Musacco-Sebio & Marisa Gabriela Repetto

  2. Departamento de Físicomatemática, Cátedra de Física, Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Buenos Aires, Argentina

    Julian Fuda & Horacio Torti

  3. Consejo Nacional de Investigaciones Científicas y Técnicas, Instituto de Bioquímica y Medicina Molecular (IBIMOL, UBA-CONICET), Buenos Aires, Argentina

    Marisa Gabriela Repetto

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  1. Fabiana Lairion
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  2. Christian Saporito-Magriñá
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  3. Rosario Musacco-Sebio
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  4. Julian Fuda
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  6. Marisa Gabriela Repetto
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Contributions

FL: validation, formal analysis, investigation, and writing—original–draft; CS-M: methodology, validation, investigation, and visualization; RM-S: methodology and investigation; JF: investigation; HT: investigation and resources; MGR: conceptualization, formal analysis, and writing—original–draft, writing, review and editing, project administration, and funding acquisition.

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Correspondence to Marisa Gabriela Repetto.

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Lairion, F., Saporito-Magriñá, C., Musacco-Sebio, R. et al. Nitric oxide, chronic iron and copper overloads and regulation of redox homeostasis in rat liver. J Biol Inorg Chem 27, 23–36 (2022). https://doi.org/10.1007/s00775-021-01908-1

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