Pehlivan Veli F, Pehlivan Basak, Duran Erdogan, Koyuncu Ismail, Erdogdu Hamza
Department of Anesthesiology and Reanimation, Faculty of Medicine, Harran University, Şanlıurfa 63200, Turkey.
Department of Medical Biochemistry, Faculty of Medicine, Harran University, Şanlıurfa 63200, Turkey.
Pharmaceuticals (Basel). 2025 Aug 19;18(8):1221. doi: 10.3390/ph18081221.
Propofol and Thiopental are widely used anesthetic agents, yet their cumulative and high-dose effects on hepatic metabolism remain insufficiently characterized. This study aimed to evaluate the impact of supra-therapeutic concentrations of these agents on carnitine and amino acid metabolism in AML12 hepatocytes, with a focus on their toxicometabolic profiles. AML12 mouse hepatocytes were exposed to escalating concentrations (2.5-500 µg/mL) of Propofol and Thiopental to assess cytotoxicity. IC values (~255 µg/mL for both) were determined, and two high-dose concentrations (100 µg/mL and 200 µg/mL) were selected for metabolic profiling. Cell viability was assessed via the MTT assay. Intracellular carnitine and amino acid levels were quantified using LC-MS/MS. Statistical analyses included one-way ANOVA with post hoc tests, unpaired -tests, and effect size estimations (Cohen's d). Propofol significantly suppressed carnitine metabolism in a dose-dependent manner, with a 79% reduction in free carnitine (C0), indicative of impaired mitochondrial β-oxidation. Thiopental, however, preserved or partially restored several acylcarnitines, including C16:1. While both agents reduced intracellular amino acid levels, 200 µg/mL Thiopental partially restored key metabolites such as glutamine, alanine, and histidine. Propofol exhibited broader metabolic suppression. Effect size analysis further confirmed the stronger inhibitory impact of Propofol. Although the concentrations used exceed typical clinical plasma levels, they may reflect prolonged or high-dose exposure scenarios observed in ICU settings. The findings highlight distinct toxicometabolic signatures for each agent and underscore the utility of metabolite profiling in modeling anesthetic-induced hepatic stress and guiding anesthetic selection in vulnerable populations.
丙泊酚和硫喷妥钠是广泛使用的麻醉剂，然而它们对肝脏代谢的累积和高剂量影响仍未得到充分表征。本研究旨在评估这些药物的超治疗浓度对AML12肝细胞中肉碱和氨基酸代谢的影响，重点关注它们的毒代代谢特征。将AML12小鼠肝细胞暴露于递增浓度（2.5 - 500μg/mL）的丙泊酚和硫喷妥钠中以评估细胞毒性。确定了IC值（两者均约为255μg/mL），并选择了两个高剂量浓度（100μg/mL和200μg/mL）进行代谢谱分析。通过MTT试验评估细胞活力。使用LC-MS/MS对细胞内肉碱和氨基酸水平进行定量。统计分析包括事后检验的单因素方差分析、非配对t检验和效应大小估计（Cohen's d）。丙泊酚以剂量依赖性方式显著抑制肉碱代谢，游离肉碱（C0）减少79%，表明线粒体β氧化受损。然而，硫喷妥钠保留或部分恢复了几种酰基肉碱，包括C16:1。虽然两种药物都降低了细胞内氨基酸水平，但200μg/mL硫喷妥钠部分恢复了关键代谢物，如谷氨酰胺、丙氨酸和组氨酸。丙泊酚表现出更广泛的代谢抑制。效应大小分析进一步证实了丙泊酚更强的抑制作用。尽管所使用的浓度超过了典型的临床血浆水平，但它们可能反映了在重症监护病房环境中观察到的长时间或高剂量暴露情况。这些发现突出了每种药物独特的毒代代谢特征，并强调了代谢物谱分析在模拟麻醉诱导的肝脏应激和指导易感人群麻醉选择方面的实用性。
