Environmental Health Science Laboratory, Sumitomo Chemical Co., Ltd., 1-98, Kasugade-naka 3-chome, Konohana-ku, Osaka 554-8558, Japan.
Environmental Health Science Laboratory, Sumitomo Chemical Co., Ltd., 1-98, Kasugade-naka 3-chome, Konohana-ku, Osaka 554-8558, Japan.
Toxicology. 2022 Apr 30;472:153160. doi: 10.1016/j.tox.2022.153160. Epub 2022 Mar 30.
Flumioxazin, is a herbicide that has inhibitory activity on protoporphyrinogen oxidase (PPO), a key enzyme in the biosynthetic pathway for heme. Flumioxazin induces anemia and developmental toxicity in rats, including ventricular septal defect and embryofetal death. Studies to elucidate the mode of action (MOA) of flumioxazin as a developmental toxicant and to evaluate its relevance to humans have been undertaken. The MOA in the rat has now been elucidated. The first key event is PPO inhibition, which results in reduced heme synthesis in embryonic erythroblasts. The critical window for this effect is gestational day 12 when almost all erythroblasts are at the polychromatophilic stage, synthesizing heme very actively. Embryonic anemia/hypoxemia is induced and the heart pumps more strongly as a compensatory action during organogenesis, leading to thinning of the ventricular walls and failure of the interventricular septum to build completely and close. Investigations showed that this MOA is specific to rats and has no relevancy to humans. Flumioxazin inhibited PPO in rat hepatocyte mitochondria more strongly than in human. A 3-dimensional molecular simulation revealed that species differences in binding affinity of flumioxazin to PPO, observed previously in vitro, were due to differences in binding free energy. In vitro studies using several types of rat and human cells (erythroblasts derived from erythroleukemia cell lines, cord blood, or pluripotent stem cells), showed that flumioxazin decreased heme synthesis in rat cells but not in human cells, demonstrating a clear, qualitative species difference. Considering all available information, including data from PBPK modelling in rat and human, as well as the fact that anemia is not a symptom in patients with variegate porphyria, a congenital hereditary PPO defect, shows that the sequence of events leading to adverse effects in the rat embryo and fetus are very unlikely to occur in humans.
氟草烟，是一种原卟啉原氧化酶（PPO）抑制剂，PPO 是血红素生物合成途径中的关键酶。氟草烟可导致大鼠贫血和发育毒性，包括室间隔缺损和胚胎死亡。为阐明氟草烟作为发育毒物的作用机制（MOA）并评估其与人类的相关性，已开展了相关研究。目前已阐明氟草烟在大鼠中的作用机制。第一个关键事件是 PPO 抑制，导致胚胎红细胞中原卟啉合成减少。此作用的关键窗口是妊娠第 12 天，此时几乎所有的红细胞都处于多色性阶段，非常活跃地合成血红素。诱导胚胎贫血/低氧血症，心脏在器官发生期间作为代偿性更强地跳动，导致心室壁变薄和室间隔不完全形成和闭合失败。研究表明，这种 MOA 是大鼠特有的，与人类无关。氟草烟在大鼠肝细胞线粒体中对 PPO 的抑制作用强于人类。三维分子模拟表明，以前在体外观察到的氟草烟与 PPO 结合亲和力的种属差异是由于结合自由能的差异。体外研究使用几种类型的大鼠和人细胞（来自红白血病细胞系、脐带血或多能干细胞的红细胞），结果表明氟草烟可减少大鼠细胞中的血红素合成，但不能减少人细胞中的血红素合成，表明存在明显的定性种属差异。考虑到所有可用信息，包括在大鼠和人中的 PBPK 模型数据，以及贫血不是杂色性卟啉症（先天性遗传性 PPO 缺陷）患者的症状这一事实，表明导致大鼠胚胎和胎儿不良影响的一系列事件在人类中极不可能发生。
