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Antioxidant Capacity Is Decreased in Wilson’s Disease and Correlates to Liver Function

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Abstract

The metabolic disorder Wilson’s disease (WD) is caused by copper accumulation in the tissues due to a biallelic pathogenic mutation of the gene ATP7B, encoding intracellular copper transporter ATPase-7B. As copper is a redox active metal; aberrations in its homeostasis may create favourable conditions for superoxide-yielding redox cycling and oxidative damage to the cells. We tried to characterise antioxidant defence in WD patients and to evaluate whether it is related to liver function. The blood glutathione concentration, the activity of manganese-SOD (MnSOD), catalase (Cat), glutathione peroxidase, and glutathione S-transferase glutathione (GST), and serum antioxidant potential (AOP-450) were measured in WD treatment-naive patients and healthy controls and correlated with clinical data. The blood glutathione concentration, the activity of MnSOD, Cat, glutathione peroxidase, and GST and AOP-450 are significantly decreased in WD patients. There was a positive correlation of AOP-450 with AST. Moreover, the Cat and GST activity as well as AOP-450 strongly correlated with parameters of synthetic liver function. MnSOD activity correlated positively with ALT and AST.The blood glutathione concentration, the activity of MnSOD, Cat, glutathione peroxidase, and GST and AOP-450 are significantly decreased in WD patients. There was a positive correlation of AOP-450 with AST. Moreover, the Cat and GST activity as well as AOP-450 strongly correlated with parameters of synthetic liver function. MnSOD activity correlated positively with ALT and AST. Liver injury in course of WD is linked with decreased antioxidant capacity.

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Abbreviations

WD:

Wilson’s disease

OMIM:

Online Mendelian Inheritance in Man

Cu:

Copper

ATP7B:

ATPase 7B

Cat:

Catalase

GPX:

Glutathione peroxidase

SOD2:

Mitochondrial magnesium superoxide dismutase

MnSOD:

Manganese superoxide dismutase

SGT:

Plasma glutathione S-transferase

References

  1. Ala A et al (2007) Wilson’s disease. Lancet 369(9559):397–408

    Article  CAS  PubMed  Google Scholar 

  2. Bitter RM et al. (2022) Structure of the Wilson disease copper transporter ATP7B. Sci Adv 8(9): p. eabl5508.

  3. Wallace DF, Dooley JS (2020) ATP7B variant penetrance explains differences between genetic and clinical prevalence estimates for Wilson disease. Hum Genet 139(8):1065–1075

    Article  CAS  PubMed  Google Scholar 

  4. Boga S, Ala A, Schilsky ML (2017) Hepatic features of Wilson disease. Handb Clin Neurol 142:91–99

    Article  PubMed  Google Scholar 

  5. Ferenci P et al (2007) Late-onset Wilson’s disease. Gastroenterology 132(4):1294–8

    Article  CAS  PubMed  Google Scholar 

  6. Ferenci P et al (2019) Age and sex but not ATP7B genotype effectively influence the clinical phenotype of wilson disease. Hepatology 69(4):1464–1476

    Article  CAS  PubMed  Google Scholar 

  7. Chen J et al (2020) The molecular mechanisms of copper metabolism and its roles in human diseases. Pflugers Arch 472(10):1415–1429

    Article  CAS  PubMed  Google Scholar 

  8. Ercal N, Gurer-Orhan H, Aykin-Burns N (2001) Toxic metals and oxidative stress part I: mechanisms involved in metal-induced oxidative damage. Curr Top Med Chem 1(6):529–39

    Article  CAS  PubMed  Google Scholar 

  9. Jomova K, Valko M (2011) Advances in metal-induced oxidative stress and human disease. Toxicology 283(2–3):65–87

    Article  CAS  PubMed  Google Scholar 

  10. Flora SJ, Shrivastava R, Mittal M (2013) Chemistry and pharmacological properties of some natural and synthetic antioxidants for heavy metal toxicity. Curr Med Chem 20(36):4540–74

    Article  CAS  PubMed  Google Scholar 

  11. Pisoschi AM, Pop A (2015) The role of antioxidants in the chemistry of oxidative stress: a review. Eur J Med Chem 97:55–74

    Article  CAS  PubMed  Google Scholar 

  12. Ali SS et al (2020) Understanding oxidants and antioxidants: classical team with new players. J Food Biochem 44(3):e13145

    Article  PubMed  Google Scholar 

  13. Gaetke LM, Chow CK (2003) Copper toxicity, oxidative stress, and antioxidant nutrients. Toxicology 189(1–2):147–63

    Article  CAS  PubMed  Google Scholar 

  14. Yucel EM et al (2021) Investigation of dynamic thiol/disulfide homeostasis and nitrosative stress in patients with Wilson disease. Turk J Gastroenterol 32(9):765–773

    Article  PubMed  Google Scholar 

  15. Ogihara H et al (1995) Plasma copper and antioxidant status in Wilson’s disease. Pediatr Res 37(2):219–26

    Article  CAS  PubMed  Google Scholar 

  16. Nagasaka H et al (2006) Relationship between oxidative stress and antioxidant systems in the liver of patients with Wilson disease: hepatic manifestation in Wilson disease as a consequence of augmented oxidative stress. Pediatr Res 60(4):472–7

    Article  CAS  PubMed  Google Scholar 

  17. Nagasaka H et al (2012) Fatty liver and anti-oxidant enzyme activities along with peroxisome proliferator-activated receptors gamma and alpha expressions in the liver of Wilson’s disease. Mol Genet Metab 107(3):542–7

    Article  CAS  PubMed  Google Scholar 

  18. Nagasaka H, Takayanagi M, Tsukahara H (2009) Children’s toxicology from bench to bed--liver injury (3): oxidative stress and anti-oxidant systems in liver of patients with Wilson disease. J Toxicol Sci 34(Suppl 2): p. SP229-36

  19. Bruha R et al (2012) Decreased serum antioxidant capacity in patients with Wilson disease is associated with neurological symptoms. J Inherit Metab Dis 35(3):541–8

    Article  CAS  PubMed  Google Scholar 

  20. Ferenci P et al (2003) Diagnosis and phenotypic classification of Wilson disease. Liver Int 23(3):139–42

    Article  PubMed  Google Scholar 

  21. Kitzberger R, Madl C, Ferenci P (2005) Wilson disease. Metab Brain Dis 20(4):295–302

    Article  PubMed  Google Scholar 

  22. Gromadzka G et al (2005) Frameshift and nonsense mutations in the gene for ATPase7B are associated with severe impairment of copper metabolism and with an early clinical manifestation of Wilson’s disease. Clin Genet 68(6):524–32

    Article  CAS  PubMed  Google Scholar 

  23. Gromadzka G et al (2010) Middle-aged heterozygous carriers of Wilson’s disease do not present with significant phenotypic deviations related to copper metabolism. J Genet 89(4):463–7

    Article  CAS  PubMed  Google Scholar 

  24. Ravin HA (1961) An improved colorimetric enzymatic assay of ceruloplasmin. J Lab Clin Med 58:161–8

    CAS  PubMed  Google Scholar 

  25. Rossi L et al (2006) Copper imbalance and oxidative stress in neurodegeneration. Ital J Biochem 55(3–4):212–21

    CAS  PubMed  Google Scholar 

  26. Yamamoto H et al (2001) In vivo evidence for accelerated generation of hydroxyl radicals in liver of Long-Evans Cinnamon (LEC) rats with acute hepatitis. Free Radic Biol Med 30(5):547–54

    Article  CAS  PubMed  Google Scholar 

  27. Jimenez I et al (2002) Chronic exposure of HepG2 cells to excess copper results in depletion of glutathione and induction of metallothionein. Toxicol In Vitro 16(2):167–75

    Article  CAS  PubMed  Google Scholar 

  28. Mukhopadhyay CK, Attieh ZK, Fox PL (1998) Role of ceruloplasmin in cellular iron uptake. Science 279(5351):714–7

    Article  CAS  PubMed  Google Scholar 

  29. Yamakura F et al (2007) In vitro preparation of iron-substituted human manganese superoxide dismutase: possible toxic properties for mitochondria. Free Radic Biol Med 43(3):423–30

    Article  CAS  PubMed  Google Scholar 

  30. Li S et al (2015) The role of oxidative stress and antioxidants in liver diseases. Int J Mol Sci 16(11):26087–124

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Dalgic B et al (2005) Evaluation of oxidant stress in Wilson’s disease and non-Wilsonian chronic liver disease in childhood. Turk J Gastroenterol 16(1):7–11

    PubMed  Google Scholar 

  32. Kalita J et al (2020) Adjunctive antioxidant therapy in neurologic Wilson’s disease improves the outcomes. J Mol Neurosci 70(3):378–385

    Article  CAS  PubMed  Google Scholar 

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Funding

This study was supported by grant N N402 375239 from the Polish National Ministry of Education and Science.

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Authors and Affiliations

  1. Faculty of Medicine, Cardinal Stefan Wyszyński University in Warsaw, Collegium Medicum, Wóycickiego 1/3, 01-938, Warsaw, Poland

    Grażyna Gromadzka

  2. Department of Gastroenterology and Internal Medicine, Medical University in Warsaw, Banacha 1a, 02-097, Warsaw, Poland

    Adam Przybyłkowski

  3. Second Department of Neurology, Institute of Psychiatry and Neurology, Sobieskiego 9, 02-957, Warsaw, Poland

    Tomasz Litwin

  4. Department of Clinical and Experimental Pharmacology, Medical University of Warsaw, Żwirki i Wigury 81, 02-091, Warsaw, Poland

    Agata Karpińska

Authors
  1. Grażyna Gromadzka
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  2. Adam Przybyłkowski
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  3. Tomasz Litwin
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  4. Agata Karpińska
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Corresponding author

Correspondence to Adam Przybyłkowski.

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Highlights

• Glutathione concentration and activity of manganese-SOD, catalase, glutathione peroxidase, and S-transferase glutathione are significantly decreased in Wilson disease patients.

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Gromadzka, G., Przybyłkowski, A., Litwin, T. et al. Antioxidant Capacity Is Decreased in Wilson’s Disease and Correlates to Liver Function. Biol Trace Elem Res 201, 1582–1587 (2023). https://doi.org/10.1007/s12011-022-03277-5

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  • DOI: https://doi.org/10.1007/s12011-022-03277-5

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