Faculdade de Farmácia, Programa de Pós-Graduação em Ciências Farmacêuticas, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil.
Serviço de Genética Médica, Hospital de Clínicas de Porto Alegre, Porto Alegre, Rio Grande do Sul, Brazil.
Cell Biochem Funct. 2023 Jun;41(4):490-500. doi: 10.1002/cbf.3800. Epub 2023 May 12.
Phenylketonuria (PKU) was the first genetic disease to have an effective therapy, which consists of phenylalanine intake restriction. However, there are patients who do not adhere to treatment and/or are not submitted to neonatal screening. PKU patients present L-carnitine (L-car) deficiency, compound that has demonstrated an antioxidant and anti-inflammatory role in metabolic diseases. This study evaluated the effect caused by exposure time to high Phe levels in PKU patients at early and late diagnosis, through pro- and anti-inflammatory cytokines, as well as the L-car effect in patients under treatment. It was observed that there was a decrease in phenylalanine levels in treated patients compared to patients at diagnosis, and an increase in L-car levels in the patients under treatment. Inverse correlation between Phe versus L-car and nitrate plus nitrite versus L-car in PKU patients was also showed. We found increased proinflammatory cytokines levels: interleukin (IL)-1β, interferons (IFN)-gamma, IL-2, tumor necrosis factor (TNF)-alpha, IL-8 and IL-6 in the patients at late diagnosis compared to controls, and IL-8 in the patients at early diagnosis and treatment compared to controls. Increased IL-2, TNF-alpha, IL-6 levels in the patients at late diagnosis compared to early diagnosis were shown, and reduced IL-6 levels in the treated patients compared to patients at late diagnosis. Moreover, it verified a negative correlation between IFN-gamma and L-car in treated patients. Otherwise, it was observed that there were increased IL-4 levels in the patients at late diagnosis compared to early diagnosis, and reduction in treated patients compared to late diagnosed patients. In urine, there was an increase in 8-isoprostane levels in the patients at diagnosis compared to controls and a decrease in oxidized guanine species in the treated patients compared to the diagnosed patients. Our results demonstrate for the first time in literature that time exposure to high Phe concentrations generates a proinflammatory status, especially in PKU patients with late diagnosis. A pro-oxidant status was verified in not treated PKU patients. Our results demonstrate the importance of early diagnosis and prompt start of treatment, in addition to the importance of L-car supplementation, which can improve cellular defense against inflammation and oxidative damage in PKU patients.
苯丙酮尿症（PKU）是第一种有有效治疗方法的遗传疾病，该方法包括限制苯丙氨酸的摄入。然而，有一些患者不遵守治疗方案，或未进行新生儿筛查。PKU 患者存在左旋肉碱（L-car）缺乏，这种化合物在代谢性疾病中表现出抗氧化和抗炎作用。本研究通过促炎和抗炎细胞因子，以及治疗患者的 L-car 作用，评估了早期和晚期诊断的 PKU 患者暴露于高苯丙氨酸水平的时间所产生的影响。结果显示，与初诊患者相比，治疗患者的苯丙氨酸水平降低，而治疗患者的 L-car 水平升高。PKU 患者中还显示了苯丙氨酸与 L-car 的负相关以及硝酸盐加亚硝酸盐与 L-car 的负相关。我们发现，与对照组相比，晚期诊断的患者促炎细胞因子白细胞介素（IL）-1β、干扰素（IFN）-γ、IL-2、肿瘤坏死因子（TNF）-α、IL-8 和 IL-6 水平升高，而早期诊断和治疗的患者中 IL-8 水平升高。与早期诊断相比，晚期诊断的患者中 IL-2、TNF-α和 IL-6 水平升高，而治疗患者的 IL-6 水平降低。此外，在治疗患者中还发现 IFN-γ与 L-car 呈负相关。相反，与早期诊断相比，晚期诊断的患者中 IL-4 水平升高，而治疗患者中 IL-4 水平降低。在尿液中，与对照组相比，初诊患者的 8-异前列腺素水平升高，与初诊患者相比，治疗患者的氧化鸟嘌呤水平降低。本研究首次在文献中证明，长时间暴露于高苯丙氨酸浓度会产生促炎状态，尤其是在晚期诊断的 PKU 患者中。在未经治疗的 PKU 患者中还发现了促氧化剂状态。我们的结果表明，早期诊断和及时开始治疗非常重要，此外，左旋肉碱的补充也非常重要，它可以改善 PKU 患者的细胞防御能力，防止炎症和氧化损伤。
