Xu Jiaqiang, Li Gao, Wang Zhuoyi, Si Luqin, He Sijie, Cai Jialing, Huang Jiangeng, Donovan Maureen D
Department of Pharmaceutics, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, PR China; Division of Pharmaceutics and Translational Therapeutics, College of Pharmacy, University of Iowa, Iowa City, IA 52242 United States.
Department of Pharmaceutics, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, PR China.
Chemosphere. 2016 Feb;145:487-94. doi: 10.1016/j.chemosphere.2015.11.062. Epub 2015 Dec 14.
Glyphosate is one of the most commonly used herbicides worldwide due to its broad spectrum of activity and reported low toxicity to humans. Glyphosate has an amino acid-like structure that is highly polar and shows low bioavailability following oral ingestion and low systemic toxicity following intravenous exposures. Spray applications of glyphosate in agricultural or residential settings can result in topical or inhalation exposures to the herbicide. Limited systemic exposure to glyphosate occurs following skin contact, and pulmonary exposure has also been reported to be low. The results of nasal inhalation exposures, however, have not been evaluated. To investigate the mechanisms of glyphosate absorption across epithelial tissues, the permeation of glyphosate across Caco-2 cells, a gastrointestinal epithelium model, was compared with permeation across nasal respiratory and olfactory tissues excised from cows. Saturable glyphosate uptake was seen in all three tissues, indicating the activity of epithelial transporters. The uptake was shown to be ATP and Na(+) independent, and glyphosate permeability could be significantly reduced by the inclusion of competitive amino acids or specific LAT1/LAT2 transporter inhibitors. The pattern of inhibition of glyphosate permeability across Caco-2 and nasal mucosal tissues suggests that LAT1/2 play major roles in the transport of this amino-acid-like herbicide. Enhanced uptake into the epithelial cells at barrier mucosae, including the respiratory and gastrointestinal tracts, may result in more significant local and systemic effects than predicted from glyphosate's passive permeability, and enhanced uptake by the olfactory mucosa may result in further CNS disposition, potentially increasing the risk for brain-related toxicities.
草甘膦是全球使用最广泛的除草剂之一，因其具有广谱活性且据报道对人类毒性较低。草甘膦具有类似氨基酸的结构，极性很强，口服后生物利用度低，静脉注射后全身毒性也低。在农业或住宅环境中喷洒草甘膦可导致局部接触或吸入该除草剂。皮肤接触后草甘膦的全身暴露有限，据报道肺部暴露也较低。然而，鼻腔吸入暴露的结果尚未得到评估。为了研究草甘膦跨上皮组织吸收的机制，将草甘膦跨胃肠道上皮模型Caco-2细胞的渗透与跨从奶牛身上切除的鼻呼吸和嗅觉组织的渗透进行了比较。在所有三种组织中均观察到草甘膦的饱和摄取，表明上皮转运体具有活性。摄取显示为不依赖ATP和Na(+)，加入竞争性氨基酸或特异性LAT1/LAT2转运体抑制剂可显著降低草甘膦的通透性。草甘膦跨Caco-2细胞和鼻黏膜组织通透性的抑制模式表明，LAT1/2在这种类似氨基酸的除草剂的转运中起主要作用。屏障黏膜（包括呼吸道和胃肠道）上皮细胞摄取增加，可能导致比根据草甘膦被动通透性预测的更显著的局部和全身效应，而嗅觉黏膜摄取增加可能导致进一步的中枢神经系统分布，潜在地增加与脑相关毒性的风险。
