Globotriaosylceramide is correlated with oxidative stress and inflammation in Fabry patients treated with enzyme replacement therapy

• Published in: Biochimica et biophysica acta Vol. 1822; no. 2; pp. 226 - 232
• Main Authors: Biancini, Giovana B., Vanzin, Camila S., Rodrigues, Daiane B., Deon, Marion, Ribas, Graziela S., Barschak, Alethéa G., Manfredini, Vanusa, Netto, Cristina B.O., Jardim, Laura B., Giugliani, Roberto, Vargas, Carmen R.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.02.2012
• Subjects: Adult; alpha-Galactosidase - metabolism; Antioxidant defense; Antioxidants - metabolism; Catalase - blood; Catalase - metabolism; Enzyme Replacement Therapy; Erythrocytes - enzymology; Erythrocytes - metabolism; Fabry disease; Fabry Disease - drug therapy; Fabry Disease - metabolism; Fabry Disease - pathology; Fabry Disease - urine; Female; Globotriaosylceramide; Glutathione - metabolism; Glutathione Peroxidase - blood; Glutathione Peroxidase - metabolism; Humans; Inflammation; Inflammation - metabolism; Inflammation - pathology; Inflammation - urine; Interleukin-6 - blood; Interleukin-6 - metabolism; Male; Malondialdehyde - blood; Malondialdehyde - metabolism; Middle Aged; Oxidative stress; Oxidative Stress - physiology; Reactive Oxygen Species - metabolism; Reactive species; Superoxide Dismutase - blood; Superoxide Dismutase - metabolism; Trihexosylceramides - metabolism; Trihexosylceramides - urine; Tumor Necrosis Factor-alpha - metabolism; Tyrosine - metabolism; Young Adult; Globotriaosylceramide; Oxidative stress; Di-Tyr; IL; Reactive species; Fabry disease; SOD; Inflammation; MDA; TNF; GPx; Cr; FU; Antioxidant defense; H 2O 2; LC-MS/MS; CAT; Gb3; GLA; GSH; FD; HPLC
• ISSN: 0925-4439; 0006-3002; 1879-260X
• DOI: 10.1016/j.bbadis.2011.11.001

Fabry disease is an X-linked inborn error of glycosphingolipid catabolism due to deficient activity of α-galactosidase A that leads to accumulation of the enzyme substrates, mainly globotriaosylceramide (Gb3), in body fluids and lysosomes of many cell types. Some pathophysiology hypotheses are intimately linked to reactive species production and inflammation, but until this moment there is no in vivo study about it. Hence, the aim of this study was to investigate oxidative stress parameters, pro-inflammatory cytokines and Gb3 levels in Fabry patients under treatment with enzyme replacement therapy (ERT) and finally to establish a possible relation between them. We analyzed urine and blood samples of patients under ERT (n = 14) and healthy age-matched controls (n = 14). Patients presented decreased levels of antioxidant defenses, assessed by reduced glutathione (GSH), glutathione peroxidase (GPx) activity and increased superoxide dismutase/catalase (SOD/CAT) ratio in erythrocytes. Concerning to the damage to biomolecules (lipids and proteins), we found that plasma levels of malondialdehyde (MDA) and protein carbonyl groups and di-tyrosine (di-Tyr) in urine were increased in patients. The pro-inflammatory cytokines IL-6 and TNF-α were also increased in patients. Urinary Gb3 levels were positively correlated with the plasma levels of IL-6, carbonyl groups and MDA. IL-6 levels were directly correlated with di-Tyr and inversely correlated with GPx activity. This data suggest that pro-inflammatory and pro-oxidant states occur, are correlated and seem to be induced by Gb3 in Fabry patients. ► We tested urine and blood samples of treated Fabry patients and compared to controls. ► Patients presented higher levels of pro-inflammatory and pro-oxidant biomarkers. ► Oxidative stress and inflammation were directly correlated with globotriaosylceramide. ► Globotriaosylceramide accumulated seems to induce these findings in vivo.