Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, UFRGS, Porto Alegre, RS, Brazil; Serviço de Genética Médica, HCPA, UFRGS, Porto Alegre, RS, Brazil.
Serviço de Genética Médica, HCPA, UFRGS, Porto Alegre, RS, Brazil; Programa de Pós-Graduação em Ciências Farmacêuticas, UFRGS, Porto Alegre, RS, Brazil.
Arch Biochem Biophys. 2020 Jan 15;679:108206. doi: 10.1016/j.abb.2019.108206. Epub 2019 Nov 22.
The mitochondrial fatty acids oxidation disorders (FAOD) are inherited metabolic disorders (IMD) characterized by the accumulation of fatty acids of different sizes of chain according to the affected enzyme.
This study evaluated the lipid peroxidation by the measurement of 8-isoprostanes, nitrosative stress parameters by the measurement of nitrite and nitrate content and DNA and RNA oxidative damage by the measurement of oxidized guanine species in urine samples from long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD), medium-chain acyl-CoA dehydrogenase deficiency (MCADD) and multiple acyl-CoA dehydrogenase deficiency (MADD) patients. Also, we analyzed the in vitro DNA damage by comet assay induced by adipic acid, suberic acid, hexanoylglycine and suberylglycine, separated and in combination, as well as the effect of l-carnitine in human leukocytes.
An increase on 8-isoprostanes levels in all groups of patients was observed. The nitrite and nitrate levels were increased in LCHADD patients. DNA and RNA damage evaluation revealed increase on oxidized guanine species levels in LCHADD and MADD patients. The in vitro evaluation revealed an increase on the DNA damage induced by all metabolites, besides a potencialyzed effect. l-carnitine decreased the DNA damage induced by the metabolites.
These results demonstrate that toxic metabolites accumulated could be related to the increased oxidative and nitrosative stress of FAOD patients and that the metabolites, separated and in combination, cause DNA damage, which was reduced by l-carnitine, demonstrating antioxidant protection.
This work demonstrated oxidative stress in FAOD patients and the genotoxic potential of MCADD metabolites and the protective effect of l-carnitine.
线粒体脂肪酸氧化障碍（FAOD）是一种遗传性代谢紊乱（IMD），其特征是根据受影响的酶积累不同大小链的脂肪酸。
本研究通过测量 8-异前列腺素来评估脂质过氧化，通过测量亚硝酸盐和硝酸盐含量来评估硝化应激参数，通过测量氧化鸟嘌呤种类来评估 DNA 和 RNA 氧化损伤在长链 3-羟酰基辅酶 A 脱氢酶缺乏症（LCHADD）、中链酰基辅酶 A 脱氢酶缺乏症（MCADD）和多酰基辅酶 A 脱氢酶缺乏症（MADD）患者的尿液样本中。此外，我们还分析了由己二酸、壬二酸、己酰甘氨酸和壬酰甘氨酸分离和组合以及左旋肉碱在人白细胞中诱导的彗星试验的体外 DNA 损伤。
所有患者组的 8-异前列腺素水平均升高。LCHADD 患者的亚硝酸盐和硝酸盐水平升高。DNA 和 RNA 损伤评估显示 LCHADD 和 MADD 患者氧化鸟嘌呤种类水平升高。体外评估显示所有代谢物均能诱导 DNA 损伤，且有潜在的增强作用。左旋肉碱降低了代谢物诱导的 DNA 损伤。
这些结果表明，积累的毒性代谢物可能与 FAOD 患者氧化应激和硝化应激增加有关，而且代谢物分离和组合会导致 DNA 损伤，而左旋肉碱可减少这种损伤，显示出抗氧化保护作用。
本研究证明了 FAOD 患者存在氧化应激，MCADD 代谢物具有遗传毒性，左旋肉碱具有保护作用。
