Metabolic Activation of Myristicin and Its Role in Cellular Toxicity,Journal of Agricultural and Food Chemistry

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Metabolic Activation of Myristicin and Its Role in Cellular Toxicity
Journal of Agricultural and Food Chemistry ( IF 5.7 ) Pub Date : 2019-03-26 00:00:00 , DOI: 10.1021/acs.jafc.9b00893
Xu Zhu _{1,

2} , Yi-Kun Wang _{1,

2} , Xiao-Nan Yang _{1,

3} , Xue-Rong Xiao ₁ , Ting Zhang _{1,

2} , Xiu-Wei Yang ₄ , Hong-Bo Qin ₁ , Fei Li _{1,

5}

Affiliation

Myristicin is widely distributed in spices and medicinal plants. The aim of this study was to explore the role of metabolic activation of myristicin in its potential toxicity through a metabolomic approach. The myristicin–N-acetylcysteine adduct was identified by comparing the metabolic maps of myristicin and 1′-hydroxymyristicin. The supplement of N-acetylcysteine could protect against the cytotoxicity of myristicin and 1′-hydroxymyristicin in primary mouse hepatocytes. When the depletion of intracellular N-acetylcysteine was pretreated with diethyl maleate in hepatocytes, the cytotoxicity induced by myristicin and 1′-hydroxymyristicin was deteriorated. It suggested that the N-acetylcysteine adduct resulting from myristicin bioactivation was closely associated with myristicin toxicity. Screening of human recombinant cytochrome P450s (CYPs) and treatment with CYP inhibitors revealed that CYP1A1 was mainly involved in the formation of 1′-hydroxymyristicin. Collectively, this study provided a global view of myristicin metabolism and identified the N-acetylcysteine adduct resulting from myristicin bioactivation, which could be used for understanding the mechanism of myristicin toxicity.

中文翻译：

肉豆蔻霉素的代谢活化及其在细胞毒性中的作用

肉豆蔻素广泛分布于香料和药用植物中。这项研究的目的是通过代谢组学方法探讨肉豆蔻苷的代谢活化在其潜在毒性中的作用。肉豆蔻素-N-乙酰半胱氨酸加合物是通过比较肉豆蔻素和1'-羟基肉豆蔻素的代谢图谱来鉴定的。N-乙酰半胱氨酸的补充可以防止肉豆蔻素和1'-羟基肉豆蔻素在原代小鼠肝细胞中的细胞毒性。当在肝细胞中用马来酸二乙酯预处理细胞内N-乙酰半胱氨酸的消耗时，由肉豆蔻苷和1'-羟基肉豆蔻苷诱导的细胞毒性恶化。它建议ñ肉豆蔻碱生物活化产生的-乙酰半胱氨酸加合物与肉豆蔻碱毒性密切相关。筛选人重组细胞色素P450（CYP）并用CYP抑制剂治疗表明CYP1A1主要参与1'-羟基肉豆蔻苷的形成。总的来说，该研究提供了肉豆蔻素代谢的整体观点，并鉴定了由肉豆蔻素生物活化产生的N-乙酰半胱氨酸加合物，其可用于理解肉豆蔻素毒性的机理。

更新日期：2019-03-26

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