Pimpão António B, Teixeira-Santos Luísa, Coelho Nuno R, Correia Maria João, Morello Judit, Antunes Alexandra M M, Monteiro Emília C, Pereira Sofia A
iNOVA4Health, NOVA Medical School | Faculdade de Ciências Médicas, NMS|FCM, Universidade NOVA de Lisboa, Lisboa, Portugal.
Centro Clínico Académico de Lisboa (CCAL), Lisboa, Portugal.
Arch Toxicol. 2025 Apr 19. doi: 10.1007/s00204-025-04044-w.
We were pioneers in describing aryl hydrocarbon receptor (AhR) activation by chronic intermittent hypoxia (CIH) in a rat pre-clinical model. This model mimics hypertension (HTN) secondary to obstructive sleep apnea, enabling longitudinal investigation of hypertension development. Concerns about the influence of barbiturates on AhR-regulated enzymes led us to opt for ketamine/medetomidine anesthesia in terminal in vivo experiments. However, the biotransformation and the metabolomic pathways of ketamine in CIH conditions, which is associated to AhR overactivation, are yet to be disclosed. A rat model of CIH was used, with experimental groups defined based on the duration of CIH exposure. Ketamine/medetomidine (75/0.5 mg/kg) was administered intraperitoneally as terminal anesthetic. Metabolomic strategies were used to reveal the profiles of ketamine and its metabolites in liver and kidney tissues, uncovering six metabolites, including the first report of norketamine glucuronide formation in the liver. While PCA analysis revealed similar ketamine metabolite fingerprints in normoxia and CIH, a predominance of hydroxynorketamine over norketamine was observed in CIH condition. A consistent association between norketamine, hydroxyketamine and the metabolome was found in both normoxia and CIH conditions. The AhR antagonist CH-223191 (5 mg/kg) influenced hydroxynorketamine glucuronidation in the liver. No changes in medetomidine biotransformation were detected. Overall, these findings expand the knowledge of ketamine metabolism and its tissue-dependence. The results emphasize the importance of considering how ketamine biotransformation may differ between control and experimental conditions in metabolic studies, particularly in chronic intermittent hypoxia conditions. The role of AhR in ketamine biotransformation is herein described for the first time.
我们是在大鼠临床前模型中描述慢性间歇性缺氧（CIH）激活芳烃受体（AhR）的先驱。该模型模拟阻塞性睡眠呼吸暂停继发的高血压（HTN），能够对高血压的发展进行纵向研究。由于担心巴比妥类药物对AhR调节酶的影响，我们在终末体内实验中选择了氯胺酮/美托咪定麻醉。然而，与AhR过度激活相关的CIH条件下氯胺酮的生物转化和代谢组学途径尚未明确。使用了CIH大鼠模型，根据CIH暴露持续时间定义实验组。腹腔注射氯胺酮/美托咪定（75/0.5 mg/kg）作为终末麻醉剂。采用代谢组学策略揭示氯胺酮及其代谢产物在肝脏和肾脏组织中的概况，发现了六种代谢产物，包括首次报道肝脏中去甲氯胺酮葡糖醛酸苷的形成。虽然主成分分析（PCA）显示常氧和CIH条件下氯胺酮代谢产物指纹相似，但在CIH条件下观察到羟基去甲氯胺酮比去甲氯胺酮占优势。在常氧和CIH条件下均发现去甲氯胺酮、羟基氯胺酮与代谢组之间存在一致的关联。AhR拮抗剂CH-223191（5 mg/kg）影响肝脏中羟基去甲氯胺酮的葡糖醛酸化。未检测到美托咪定生物转化的变化。总体而言，这些发现扩展了对氯胺酮代谢及其组织依赖性的认识。结果强调了在代谢研究中，尤其是在慢性间歇性缺氧条件下，考虑氯胺酮生物转化在对照和实验条件之间可能存在差异的重要性。本文首次描述了AhR在氯胺酮生物转化中的作用。
