Glufosinate (ammonium salt) is a key herbicide to manage weeds, which is formulated as a racemic mixture of d, l-phosphinothricin [1]. Glufosinate inhibits glutamine synthetase (GS), leading to the accumulation of ammonia and metabolites from the photorespiration pathway (such as acetic acid and malonic acid), as well as the consumption of other intermediates (such as glycine, serine, hydroxypropionic acid, and glyeraldehyde), and causes a significant accumulation of reactive oxygen species (ROS), resulting in the rapid death of plant cells[2]. Glufosinate has been widely used to inhibit the formation of glutamine and to regulate the seed components of soybean varieties[3].
In vitro, Glufosinate treatment (0.5µg/ml) for 72 hours significantly increased the frequencies of chromosome aberration and micronucleus in human lymphocytes [4]. Treatment with 100µM Glufosinate for 12 days increased the expression of neurogenic protein 2 in mouse neural stem cells (NSCs) and altered the glial differentiation of NSCs [5]. Treatment with 10µg/ml Glufosinate for 24 hours induced apoptosis of mouse embryonic neuroepithelial cells, characterized by fragmentation of DNA and condensation and separation of chromatin[6]. Treatment with 10µg/ml Glufosinate for 1 hour inhibited the mitochondrial function of human sperm cells, by decreasing the oxygen consumption rate in the active and in the passive state of mitochondrial respiration [7].
In vivo, Glufosinate treatment via oral administration at a dose of 20mg/kg (twice a day) for 14 days reduced the levels of GS in the tumors of Lewis lung carcinoma (LLC) cell-xenograft mouse models, decreased the lung metastases, and induced the aggregation of cytotoxic T lymphocytes and the normalization of tumor blood vessels[8].
References:
[1] Takano H K, Dayan F E. Glufosinate‐ammonium: a review of the current state of knowledge[J]. Pest Management Science, 2020, 76(12): 3911-3925.
[2] Takano H K, Beffa R, Preston C, et al. A novel insight into the mode of action of glufosinate: how reactive oxygen species are formed[J]. Photosynthesis Research, 2020, 144(3): 361-372.
[3] Reddy K N, Zablotowicz R M, Bellaloui N, et al. Glufosinate Effects on Nitrogen Nutrition, Growth, Yield, and Seed Composition in Glufosinate‐Resistant and Glufosinate‐Sensitive Soybean[J]. International Journal of Agronomy, 2011, 2011(1): 109280.
[4] Santovito A, Ruberto S, Gendusa C, et al. In vitro evaluation of genomic damage induced by glyphosate on human lymphocytes[J]. Environmental Science and Pollution Research, 2018, 25(34): 34693-34700.
[5] Feat-Vetel J, Larrigaldie V, Meyer-Dilhet G, et al. Multiple effects of the herbicide glufosinate-ammonium and its main metabolite on neural stem cells from the subventricular zone of newborn mice[J]. Neurotoxicology, 2018, 69: 152-163.
[6] Watanabe T. Apoptosis induced by glufosinate ammonium in the neuroepithelium of developing mouse embryos in culture[J]. Neuroscience letters, 1997, 222(1): 17-20.
[7] Ferramosca A, Lorenzetti S, Di Giacomo M, et al. Herbicides glyphosate and glufosinate ammonium negatively affect human sperm mitochondria respiration efficiency[J]. Reproductive Toxicology, 2021, 99: 48-55.
[8] Menga A, Serra M, Todisco S, et al. Glufosinate constrains synchronous and metachronous metastasis by promoting anti‐tumor macrophages[J]. EMBO Molecular Medicine, 2020, 12(10): EMMM201911210.
Glufosinate (ammonium salt)是一种用于杂草治理的关键除草剂，是D,L-phosphinothricin的外消旋混合物[1]。Glufosinate通过抑制谷氨酰胺合成酶（GS），促进氨和光呼吸途径代谢物（如乙酸和丙二酸）积累，并消耗其他中间产物（如甘氨酸、丝氨酸、羟基丙酸和甘油醛），同时引起活性氧（ROS）的大量积累，从而导致植物细胞快速死亡[2]。Glufosinate已被广泛用于抑制谷氨酰胺的形成，并调节大豆品种的种子组分[3]。
在体外，0.5µg/ml的Glufosinate处理人淋巴细胞72小时，显著增加了染色体畸变和微核的频率[4]。100µM的Glufosinate处理小鼠神经干细胞（NSCs）12天，增加了neurogenic protein 2的表达，并改变了NSCs的胶质分化[5]。10µg/ml的Glufosinate处理小鼠胚胎神经上皮细胞24小时，诱导了细胞凋亡，表现为DNA断裂以及染色质凝聚和分离[6]。10µg/ml的Glufosinate处理人精子细胞1小时，通过降低线粒体呼吸在活跃状态和静息状态下的耗氧率，抑制了精子细胞的线粒体功能[7]。
在体内，每日两次口服20mg/kg剂量的Glufosinate，连续14天，降低了Lewis lung carcinoma (LLC)细胞异种移植小鼠模型肿瘤中的GS水平，减少了肺转移灶，并诱导了细胞毒性T淋巴细胞的聚集和肿瘤血管的正常化[8]。