Comparative hepatotoxicity of a herbicide, epyrifenacil, in humans and rodents by comparing the dynamics and kinetics of its causal metabolite.

IF 1.5 4区 农林科学 Q2 ENTOMOLOGY Journal of Pesticide Science Pub Date : 2021-11-20 DOI:10.1584/jpestics.D21-026
Kohei Matsunaga, Satoki Fukunaga, Jun Abe, Hayato Takeuchi, Sachiko Kitamoto, Yoshitaka Tomigahara
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引用次数: 3

Abstract

A new herbicide, epyrifenacil (S-3100), inhibits protoporphyrinogen oxidase (PPO) in plants. Repeated administration of epyrifenacil in laboratory animals led to some toxicological changes related to PPO inhibition, e.g., hepatotoxicity caused by porphyrin accumulation and anemia caused by the inhibition of heme biosynthesis. In vitro studies revealed that an ester-cleaved metabolite, S-3100-CA, is predominant in mammals, exhibits PPO-inhibitory activity, and thus is the cause of epyrifenacil-induced toxicity. To assess the human risk, the effects of species differences on the dynamics (PPO inhibition) and kinetics (liver uptake) of epyrifenacil were evaluated separately. The results of in vitro assays revealed an approximately tenfold weaker inhibition of PPO by S-3100-CA in humans than in rodents and six- to thirteen-fold less hepatic uptake of S-3100-CA in humans than in mice. Finally, it was suggested that humans are less sensitive to the toxicity of epyrifenacil than are rodents, although further mechanistic research is highly anticipated.

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通过比较其代谢物的动力学和动力学,比较除草剂依昔那那对人类和啮齿动物的肝毒性。
epyrifenil (S-3100)是一种抑制植物原卟啉原氧化酶(PPO)的除草剂。在实验动物中反复给药会导致一些与PPO抑制有关的毒理学变化,如卟啉积累引起的肝毒性和抑制血红素生物合成引起的贫血。体外研究表明,酯裂解代谢物S-3100-CA在哺乳动物中占主导地位,表现出ppo抑制活性,因此是吡利那西诱导毒性的原因。为了评估人类风险,我们分别评估了物种差异对epyrifenil动力学(PPO抑制)和动力学(肝脏摄取)的影响。体外实验结果显示,S-3100-CA对人体PPO的抑制作用比啮齿动物弱约10倍,人体对S-3100-CA的肝脏摄取比小鼠少6至13倍。最后,有人认为,人类对表利那克利的毒性比啮齿动物更不敏感,尽管进一步的机制研究是高度期待的。
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来源期刊
Journal of Pesticide Science
Journal of Pesticide Science 农林科学-昆虫学
CiteScore
4.30
自引率
4.20%
发文量
28
审稿时长
18-36 weeks
期刊介绍: The Journal of Pesticide Science publishes the results of original research regarding the chemistry and biochemistry of pesticides including bio-based materials. It also covers their metabolism, toxicology, environmental fate and formulation.
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