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Oxidative Stress in Homocystinuria Due to Cystathionine ß-Synthase Deficiency: Findings in Patients and in Animal Models

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Abstract

Homocystinuria is an inborn error of amino acid metabolism caused by deficiency of cystathionine ß-synthase (CBS) activity, biochemically characterized by homocysteine (Hcy) and methionine (Met) accumulation in biological fluids and high urinary excretion of homocystine. Clinical manifestations include thinning and lengthening of long bones, osteoporosis, dislocation of the ocular lens, thromboembolism, and mental retardation. Although the pathophysiology of this disease is poorly known, the present review summarizes the available experimental findings obtained from patients and animal models indicating that oxidative stress may contribute to the pathogenesis of homocystinuria. In this scenario, several studies have shown that enzymatic and non-enzymatic antioxidant defenses are decreased in individuals affected by this disease. Furthermore, markers of lipid, protein, and DNA oxidative damage have been reported to be increased in blood, brain, liver, and skeletal muscle in animal models studied and in homocystinuric patients, probably as a result of increased free radical generation. On the other hand, in vitro and in vivo studies have shown that Hcy induces reactive species formation in brain, so that this major accumulating metabolite may underlie the oxidative damage observed in the animal model and human condition. Taken together, it may be presumed that the disruption of redox homeostasis may contribute to the tissue damage found in homocystinuria. Therefore, it is proposed that the use of appropriate antioxidants may represent a novel adjuvant therapy for patients affected by this disease.

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Abbreviations

4-HNE:

4-hydroxyalkenal

AChE:

Acetylcholinesterase

ALT:

Alanine aminotransferase

ApoA-1:

Apolipoprotein A1

AST:

Aspartate aminotransferase

BuChE:

Butyrylcholinesterase

CAT:

Catalase

CBS:

Cystathionine ß-synthase

DCF:

2′,7′-dichlorofluorescein

EC-SOD:

Extracellular superoxide dismutase

G6PD:

Glucose 6-phosphate dehydrogenase

GPx:

Glutathione peroxidase

GRed:

Glutathione reductase

GSH:

Glutathione

GST:

Glutathione S-transferase

H2O2 :

Hydrogen peroxide

Hcy:

Homocysteine

Hhcy:

Hyperhomocysteinemia

IEM:

Inborn errors of metabolism

IFN-γ:

Interferon-γ

IL-1β:

Interleukin-1β

IL-6:

Interleukin-6

MDA:

Malondialdehyde

Met:

Methionine

MTHFR:

Methylenetetrahydrofolate reductase

O2 − :

Superoxide anion

PKA:

Protein kinase A

PON1:

Paraoxonase

RNS:

Reactive nitrogen species

ROS:

Reactive oxygen species

SOD:

Superoxide dismutase

TAR:

Total antioxidant reactivity

TAS:

Total antioxidant status

TBARS:

Thiobarbituric acid reactive substances

TRAP:

Total radical-trapping antioxidant potential

TUNEL:

Terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate biotin nick end labeling

Vitamin B6:

Pyridoxine

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Acknowledgements

This work was supported by Brazilian Foundation Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Comissão de Aperfeiçoamento de Pessoal do Nível Superior (CAPES), and Fundo de Incentivo à Pesquisa e Eventos (FIPE/HCPA).

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Authors and Affiliations

  1. Departamento de Análises, Faculdade de Farmácia, UFRGS, Avenida Ipiranga 2752, Porto Alegre, RS, 90610-000, Brazil

    Jéssica Lamberty Faverzani, Tatiane Grazieli Hammerschmidt & Carmen Regla Vargas

  2. Programa de Pós-Graduação em Ciências Biológicas Bioquímica, UFRGS, Rua Ramiro Barcelos, 2600, Porto Alegre, RS, 90035-003, Brazil

    Moacir Wajner & Carmen Regla Vargas

  3. Programa de Pós-Graduação em Ciências Farmacêuticas, UFRGS, Av. Ipiranga, 2752, Porto Alegre, RS, 90610-000, Brazil

    Marion Deon & Carmen Regla Vargas

  4. Serviço de Genética Médica HCPA, Rua Ramiro Barcelos, 2350, Porto Alegre, RS, 90035-003, Brazil

    Jéssica Lamberty Faverzani, Tatiane Grazieli Hammerschmidt, Angela Sitta, Marion Deon, Moacir Wajner & Carmen Regla Vargas

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  1. Jéssica Lamberty Faverzani
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  2. Tatiane Grazieli Hammerschmidt
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  3. Angela Sitta
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Correspondence to Carmen Regla Vargas.

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Faverzani, J.L., Hammerschmidt, T.G., Sitta, A. et al. Oxidative Stress in Homocystinuria Due to Cystathionine ß-Synthase Deficiency: Findings in Patients and in Animal Models. Cell Mol Neurobiol 37, 1477–1485 (2017). https://doi.org/10.1007/s10571-017-0478-0

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