Department of Inorganic Chemistry, Analytical Chemistry and Electrochemistry, Faculty of Chemistry, Silesian University of Technology, B. Krzywoustego 6, 44-100, Gliwice, Poland.
Department of Inorganic Chemistry, Analytical Chemistry and Electrochemistry, Faculty of Chemistry, Silesian University of Technology, B. Krzywoustego 6, 44-100, Gliwice, Poland.
Chemosphere. 2022 Jan;286(Pt 1):131592. doi: 10.1016/j.chemosphere.2021.131592. Epub 2021 Jul 19.
Nitisinone (NTBC) is currently used for the treatment of tyrosinemia type 1, a rare disease. It also exhibits potential in the treatment of other orphan diseases as well as nervous system disorders - this is however limited by its side effects. In all living organisms, NTBC inhibits 4-hydroxyphenylpyruvate dioxygenase activity, thereby affecting l-tyrosine (L-TYR) catabolism, which results in the therapeutic effect. The NTBC metabolites formed in patient's body is one of the causes of its side effects. The influence of NTBC and its metabolites; 2-amino-4-(trifluoromethyl)benzoic acid, 2-nitro-4-(trifluoromethyl)benzoic acid, and cyclohexane-1,3-dione on L-TYR catabolism was investigated in Raphanus sativus var. longipinnatus. Based on targeted LC-MS/MS analysis the concentration of NTBC and its metabolites in exposed plant tissues was determined. Based on non-targeted LC-MS/MS analysis the concentrations of products of L-TYR catabolism: levodopa, epinephrine, norepinephrine, normetanephrine, dopamine, tyramine and vitamins C, B5 and B6, additionally leucine and valine were identified as influenced by the NTBC or its metabolites. NTBC and its metabolites influenced L-TYR catabolism differently. Particularly significant changes were found in the content of epinephrine and normetanephrine: in the plant tissues exposed to NTBC, an increase in the content of these neurotransmitters was found (+42%), whereas in the plant treated with 2-amino-4-(trifluoromethyl)benzoic acid or 2-nitro-4-(trifluoromethyl)benzoic acid a decrease in concentration (-39% and 55%, respectively) was observed. Cyclohexane-1,3-dione does not influence epinephrine and normetanephrine concentration. The conclusions of this study provide a platform for expanded research on the causes of side effects of NTBC treatment.
尼替西农（NTBC）目前用于治疗 1 型酪氨酸血症，这是一种罕见疾病。它在治疗其他孤儿病和神经系统疾病方面也具有潜力——但这受到其副作用的限制。在所有生物体中，NTBC 抑制 4-羟基苯丙酮酸双加氧酶的活性，从而影响 L-酪氨酸（L-TYR）的分解代谢，从而产生治疗效果。在患者体内形成的 NTBC 代谢物是其副作用的原因之一。本研究以 Raphanus sativus var. longipinnatus 为研究对象，考察了 NTBC 及其代谢物 2-氨基-4-（三氟甲基）苯甲酸、2-硝基-4-（三氟甲基）苯甲酸和环己烷-1,3-二酮对 L-TYR 分解代谢的影响。基于靶向 LC-MS/MS 分析，测定了暴露于植物组织中的 NTBC 及其代谢物的浓度。基于非靶向 LC-MS/MS 分析，鉴定了 L-TYR 分解代谢产物的浓度：左旋多巴、肾上腺素、去甲肾上腺素、去甲肾上腺素、多巴胺、酪胺和维生素 C、B5 和 B6，此外还鉴定出亮氨酸和缬氨酸受 NTBC 或其代谢物的影响。NTBC 及其代谢物对 L-TYR 分解代谢的影响不同。在肾上腺素和去甲肾上腺素的含量上发现了特别显著的变化：在暴露于 NTBC 的植物组织中，这些神经递质的含量增加（+42%），而在用 2-氨基-4-（三氟甲基）苯甲酸或 2-硝基-4-（三氟甲基）苯甲酸处理的植物中，浓度降低（分别为-39%和-55%）。环己烷-1,3-二酮不影响肾上腺素和去甲肾上腺素的浓度。本研究的结论为进一步研究 NTBC 治疗副作用的原因提供了一个平台。
