Abstract

Thiocarbamates are a major class of herbicides that were used extensively in the agricultural industry. Toxicological evaluation showed molinate caused reproductive impairment in male rats, whilst others produced behavioural effects at high doses. Rats dosed with molinate either as a single large oral dose of 100 mg/kg or as multiple doses of 50 mg/kg for 7 days produced inhibition of brain acetylcholinesterase (AChE). Molinate and other thiocarbamate herbicides undergo metabolism to form sulphoxides that can carbamoylate thiol’s such as glutathione and proteins. We have chemically synthesised the sulphoxide and sulphone metabolites of six thiocarbamate herbicides and examined their ability to inhibit rat brain and human red cell AChE in vitro. Parent thiocarbamates were inactive, whilst the sulphoxides produced inhibition with IC₅₀’s in the 1–10 mM range, the sulphone metabolites were the most active with IC₅₀’s for molinate, pebulate, EPTC and vernolate in the μM range. Inhibition was both time- and dose-dependent with biomolecular rate constants for the inhibition of the human red cell enzyme of 0.3 × 10² and 2.0 × 10² M⁻¹ min⁻¹ for molinate sulphoxide and sulphone, respectively. No recovery of enzyme activity, with either enzyme, was seen following dilution of the inhibitor to a concentration that does not inhibit the enzyme for up to 24 h at 25°C at pH 7.4. The metabolites of these thiocarbamate herbicides are rather poor inhibitors of AChE when compared to the organophosphorus ester, paraoxon or the monomethylcarbamate, eserine. Unlike eserine the inhibition produced by the thiocarbamates is irreversible.

中文翻译：

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硫代氨基甲酸酯类除草剂对大鼠脑和人红细胞乙酰胆碱酯酶的抑制作用

摘要

硫代氨基甲酸酯是一类广泛用于农业的除草剂。毒理学评估显示禾草胺导致雄性大鼠的生殖障碍，而其他人在高剂量时会产生行为影响。大鼠以 100 毫克/千克的单次大剂量口服或以 50 毫克/千克的多剂量给药 7 天，对脑乙酰胆碱酯酶 (AChE) 产生抑制作用。禾草胺和其他硫代氨基甲酸酯类除草剂经过代谢形成亚砜，可以将硫醇（如谷胱甘肽和蛋白质）氨基甲酰化。我们化学合成了六种硫代氨基甲酸酯类除草剂的亚砜和砜代谢物，并在体外检测了它们抑制大鼠脑和人红细胞 AChE的能力. 母体硫代氨基甲酸盐是无活性的，而亚砜产生抑制作用，IC ₅₀在 1-10 mM 范围内，砜代谢物在 μM 范围内对禾草酸、pebulate、EPTC 和 Vernolate 的IC ₅₀最活跃。抑制是时间和剂量依赖性的，抑制人红细胞酶的生物分子速率常数为 0.3 × 10 ²和 2.0 × 10 ²  M ^-1  min ^-1分别为禾草胺亚砜和砜。在将抑制剂稀释至在 25°C 和 pH 7.4 条件下最多 24 小时不抑制酶的浓度后，两种酶均未观察到酶活性的恢复。与有机磷酯、对氧磷或单甲基氨基甲酸酯、丝氨酸相比，这些硫代氨基甲酸酯类除草剂的代谢物对 AChE 的抑制作用相当差。与丝氨酸不同，硫代氨基甲酸盐产生的抑制作用是不可逆的。