Gong Bowen, Zhang Shiyu, Wang Xin, Ran Guangyun, Zhang Xiaohong, Xi Jing, Gao Zhenna, Lei Yuyang, Pan Jie, Liu Ying, Luan Yang, Zhang Xinyu, Peng Ying, Li Weiwei, Zheng Jiang
State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Provincial Key Laboratory of Pharmaceutics, Guizhou Medical University, Guiyang, Guizhou 550004, P. R. China.
School of Basic Medical Sciences, Guizhou Medical University, Guiyang, Guizhou 550004, P. R. China.
J Agric Food Chem. 2023 Feb 8. doi: 10.1021/acs.jafc.2c07939.
Pyrrolizidine alkaloids (PAs) are the most common toxins of plant origin, and it is evident that PAs pollute soil, water, nearby plants, and derived foods. Cases of human poisoning due to ingestion of PA-contaminated foods have been reported in several countries. Monocrotaline (MCT) is a pyrrolizidine alkaloid from the plants of genus that causes hepatic and cardiopulmonary toxicities, and the exhibition of the toxicities requires the metabolic activation by CYP3A4 to form electrophilic dehydro-monocrotaline (DHM). The present study demonstrated that myeloperoxidase (MPO) also participated in the bioactivation of MCT. -Chloromonocrotaline was detected in both HClO/MCT incubations and MPO/HO/MgCl/MCT incubations. DHM-derived -acetylcysteine (NAC) conjugates were detected in the above incubations fortified with NAC. Lipopolysaccharide-induced inflammation in mice resulted in an elevated level of hepatic MPO activity, increased metabolic activation of MCT, and intensified elevation of serum ALT and AST activity induced by MCT. MPO inhibitor 4-aminobenzoic acid hydrazide was found to reverse these alterations. -KO mice were resistant to the observed potentiating effect of inflammation on MCT-induced liver injury. In conclusion, inflammation intensified MCT-induced liver injury. MPO participated in the observed potentiating effect of inflammation on the hepatotoxicity induced by MCT.
吡咯里西啶生物碱（PAs）是最常见的植物源毒素，很明显，PAs污染土壤、水、附近的植物及其衍生食品。多个国家都报告了因摄入受PA污染的食物而导致人体中毒的案例。野百合碱（MCT）是一种来自某属植物的吡咯里西啶生物碱，会引起肝脏和心肺毒性，而这些毒性的表现需要通过CYP3A4进行代谢活化以形成亲电的脱氢野百合碱（DHM）。本研究表明，髓过氧化物酶（MPO）也参与了MCT的生物活化过程。在HClO/MCT孵育体系以及MPO/HO/MgCl/MCT孵育体系中均检测到了氯代野百合碱。在上述添加了N-乙酰半胱氨酸（NAC）的孵育体系中检测到了DHM衍生的NAC缀合物。脂多糖诱导的小鼠炎症导致肝脏MPO活性水平升高、MCT的代谢活化增加，以及MCT诱导的血清谷丙转氨酶（ALT）和谷草转氨酶（AST）活性升高加剧。发现MPO抑制剂4-氨基苯甲酸酰肼可逆转这些改变。MPO基因敲除小鼠对观察到的炎症对MCT诱导的肝损伤的增强作用具有抗性。总之，炎症加剧了MCT诱导的肝损伤。MPO参与了观察到的炎症对MCT诱导的肝毒性的增强作用。
