关键词: Amoxapine Bacterial β-glucuronidase inhibitor Drug-induced enteropathy Dysbiosis Mycophenolic acid

Mesh : Mycophenolic Acid / metabolism pharmacology Gastrointestinal Microbiome / drug effects Glucuronidase / metabolism antagonists & inhibitors Humans Animals Mice Glucuronides / metabolism Caco-2 Cells Biotransformation Male Immunosuppressive Agents / pharmacology toxicity metabolism Intestinal Diseases / chemically induced drug therapy metabolism microbiology Cell Proliferation / drug effects Glycoproteins

来  源:   DOI:10.1016/j.lfs.2024.122792

Abstract:
OBJECTIVE: Drug-induced enteropathy is often associated with the therapeutic use of certain glucuronidated drugs. One such drug is mycophenolic acid (MPA), a well-established immunosuppressant of which gastrointestinal adverse effects are a major concern. The role of bacterial β-glucuronidase (β-G) from the gut microbiota in MPA-induced enteropathy has recently been discovered. Bacterial β-G hydrolyzes MPAG, the glucuronide metabolite of MPA excreted in the bile, leading to the digestive accumulation of MPA that would favor in turn these adverse events. We therefore hypothesized that taming bacterial β-G activity might reduce MPA digestive exposure and prevent its toxicity.
METHODS: By using a multiscale approach, we evaluated the effect of increasing concentrations of MPA on intestinal epithelial cells (Caco-2 cell line) viability, proliferation, and migration. Then, we investigated the inhibitory properties of amoxapine, a previously described bacterial β-G inhibitor, by using molecular dynamics simulations, and evaluated its efficiency in blocking MPAG hydrolysis in an Escherichia coli-based β-G activity assay. The pharmacological effect of amoxapine was evaluated in a mouse model.
RESULTS: We observed that MPA impairs intestinal epithelial cell homeostasis. Amoxapine efficiently blocks the hydrolysis of MPAG to MPA and significantly reduces digestive exposure to MPA in mice. As a result, administration of amoxapine in MPA-treated mice significantly attenuated gastrointestinal lesions.
CONCLUSIONS: Collectively, these results suggest that the digestive accumulation of MPA is involved in the pathophysiology of MPA-gastrointestinal adverse effects. This study provides a proof-of-concept of the therapeutic potential of bacterial β-G inhibitors in glucuronidated drug-induced enteropathy.
摘要:
目的:药物诱导的肠病通常与某些葡萄糖醛酸化药物的治疗应用有关。一种这样的药物是霉酚酸(MPA),一种公认的免疫抑制剂,其胃肠道不良反应是主要问题。最近发现了来自肠道微生物群的细菌β-葡糖醛酸糖苷酶(β-G)在MPA诱导的肠病中的作用。细菌β-G水解MPAG,MPA的葡萄糖醛酸代谢产物在胆汁中排泄,导致MPA的消化积累,这反过来又有利于这些不良事件。因此,我们假设驯服细菌β-G活性可能会减少MPA的消化暴露并防止其毒性。
方法:通过使用多尺度方法,我们评估了增加浓度的MPA对肠上皮细胞(Caco-2细胞系)活力的影响,扩散,和移民。然后,我们研究了阿莫沙平的抑制特性,先前描述的细菌β-G抑制剂,通过使用分子动力学模拟,并在基于大肠杆菌的β-G活性测定中评估了其阻断MPAG水解的效率。在小鼠模型中评价阿莫沙平的药理作用。
结果:我们观察到MPA损害肠上皮细胞稳态。阿莫沙平可有效阻断MPAG水解为MPA,并显着减少小鼠对MPA的消化暴露。因此,在MPA治疗的小鼠中施用阿莫沙平可显着减轻胃肠道病变。
结论:总的来说,这些结果表明,MPA的消化积累参与了MPA胃肠道不良反应的病理生理过程。这项研究提供了细菌β-G抑制剂在葡萄糖醛酸化药物诱导的肠病中的治疗潜力的概念验证。
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