DNA damage in homocystinuria: 8-oxo‑,8‑dihydro‑2’-deoxyguanosine levels in cystathionine-β-synthase deficient patients and the in vitro protective effect of N-acetyl‑L‑cysteine

Authors

  • Camila Simioni Vanzin Postgraduate Program in Biological Sciences: Biochemistry, Universidade Federal do Rio Grande do Sul (UFRGS). Porto Alegre, RS, Brasil. Medical Genetics Service, Hospital de Clínicas de Porto Alegre (HCPA). Porto Alegre, RS, Brasil.
  • Caroline Paula Mescka Medical Genetics Service, Hospital de Clínicas de Porto Alegre (HCPA). Porto Alegre, RS, Brasil.
  • Bruna Donida Postgraduate Program in Biological Sciences: Biochemistry, Universidade Federal do Rio Grande do Sul (UFRGS). Porto Alegre, RS, Brasil.
  • Desirèe Padilha Marchetti Postgraduate Program in Biological Sciences: Biochemistry, Universidade Federal do Rio Grande do Sul (UFRGS). Porto Alegre, RS, Brasil.
  • Carlos Eduardo Jacques Postgraduate Program in Biological Sciences: Biochemistry, Universidade Federal do Rio Grande do Sul (UFRGS). Porto Alegre, RS, Brasil.
  • Tatiane Hauschild Postgraduate Program in Pharmaceutical Sciences, Universidade Federal do Rio Grande do Sul (UFRGS). Porto Alegre, RS, Brasil.
  • Jéssica Lamberty Faverzani Medical Genetics Service, Hospital de Clínicas de Porto Alegre (HCPA). Porto Alegre, RS, Brasil.
  • Marion Deon Postgraduate Program in Pharmaceutical Sciences, Universidade Federal do Rio Grande do Sul (UFRGS). Porto Alegre, RS, Brasil.
  • Dinara Moura Laboratory of Toxicological Genetics, Universidade Federal de Ciências de Saúde de Porto Alegre (UFCSPA). Porto Alegre, RS, Brasil.
  • Jenifer Saffi Laboratory of Toxicological Genetics, Universidade Federal de Ciências de Saúde de Porto Alegre (UFCSPA). Porto Alegre, RS, Brasil.
  • Daniella de Moura Coelho Medical Genetics Service, Hospital de Clínicas de Porto Alegre (HCPA). Porto Alegre, RS, Brasil.
  • Moacir Wajner Postgraduate Program in Biological Sciences: Biochemistry, Universidade Federal do Rio Grande do Sul (UFRGS). Porto Alegre, RS, Brasil. Medical Genetics Service, Hospital de Clínicas de Porto Alegre (HCPA). Porto Alegre, RS, Brasil.
  • Angela T.S. Wyse Postgraduate Program in Biological Sciences: Biochemistry, Universidade Federal do Rio Grande do Sul (UFRGS). Porto Alegre, RS, Brasil.
  • Carmen Regla Vargas Postgraduate Program in Biological Sciences: Biochemistry, Universidade Federal do Rio Grande do Sul (UFRGS). Porto Alegre, RS, Brasil. Medical Genetics Service, Hospital de Clínicas de Porto Alegre (HCPA). Porto Alegre, RS, Brasil. Postgraduate Program in Pharmaceutical Sciences, Universidade Federal do Rio Grande do Sul (UFRGS). Porto Alegre, RS, Brasil.

Keywords:

Cystathionine-β-synthase deficiency, oxidative stress, 8-oxo-7, 8-dihydro- 2’-deoxyguanosine, homocysteine, DNA damage, N-acetyl-L-cysteine

Abstract

Introduction: Homocysteine (Hcy) tissue accumulation occurs in a metabolic disease characterized biochemically by cystathionine β-synthase (CBS) deficiency and clinically by mental retardation, vascular problems, and skeletal abnormalities. Previous studies indicate the occurrence of DNA damage secondary to hyperhomocysteinemia and it was observed that DNA damage occurs in leukocytes from CBS-deficient patients. This study aimed to investigate whether an oxidative mechanism could be involved in DNA damage previously found and investigated the in vitro effect of N-acety-L-cysteine (NAC) on DNA damage caused by high Hcy levels.

Methods: We evaluated a biomarker of oxidative DNA damage in the urine of CBS‑deficient patients, as well as the in vitro effect of NAC on DNA damage caused by high levels of Hcy. Moreover, a biomarker of lipid oxidative damage was also measured in urine of CBS deficient patients.

Results: There was an increase in parameters of DNA (8-oxo-7,8-dihydro-2’- deoxyguanosine) and lipid (15-F2t-isoprostanes levels) oxidative damage in CBS-deficient patients when compared to controls. In addition, a significant positive correlation was found between 15-F2t-isoprostanes levels and total Hcy concentrations. Besides, an in vitro protective effect of NAC at concentrations of 1 and 5 mM was observed on DNA damage caused by Hcy 50 μM and 200 μM. Additionally, we showed a decrease in sulfhydryl content in plasma from CBS-deficient patients when compared to controls.

Discussion: These results demonstrated that DNA damage occurs by an oxidative mechanism in CBS deficiency together with lipid oxidative damage, highlighting the NAC beneficial action upon DNA oxidative process, contributing with a new treatment perspective of the patients affected by classic homocystinuria.

Keywords: Cystathionine-β-synthase deficiency; oxidative stress; 8-oxo-7,8-dihydro- 2’-deoxyguanosine; homocysteine; DNA damage; N-acetyl-L-cysteine 

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Published

2018-04-11

How to Cite

1.
Vanzin CS, Mescka CP, Donida B, Marchetti DP, Jacques CE, Hauschild T, Faverzani JL, Deon M, Moura D, Saffi J, Coelho D de M, Wajner M, Wyse AT, Vargas CR. DNA damage in homocystinuria: 8-oxo‑,8‑dihydro‑2’-deoxyguanosine levels in cystathionine-β-synthase deficient patients and the in vitro protective effect of N-acetyl‑L‑cysteine. Clin Biomed Res [Internet]. 2018Apr.11 [cited 2022May19];38(1). Available from: https://seer.ufrgs.br/index.php/hcpa/article/view/76977

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Original Articles