British journal of pharmacology · 2026
Sodium valproate induces pancreatic injury by disruption of one-carbon metabolism.
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Cai Wenhao, Wu Di, Li Yuying, Chvanov Michael, Awais Muhammad, Forootan Shiva Seyed, Meng Xiaoli, Latawiec Diane, Brown Joseph P, Li Ziyu, He Wenhua, Evans Anthony, Mukherjee Rajarshi, Szatmary Peter, Criddle David N, Goldring Chris, Huang Wei, Xia Qing, Sutton Robert
Аннотация
BACKGROUND AND PURPOSE: Valproate medications are a leading cause of drug-associated acute pancreatitis. This study examines how sodium valproate (Na-VPA) induces pancreatic injury and contributes to acute pancreatitis (AP).
EXPERIMENTAL APPROACH: Murine pancreatic acinar cells (PACs) were treated with Na-VPA or major VPA metabolites, and cytotoxicity was assessed by spectrofluorometry and confocal imaging. In vivo, C57BL/6 mice, with or without caerulein-induced pancreatitis (CER-AP), were administered Na-VPA and pancreatic injury was evaluated. Intracellular methionine-cycle metabolites were quantified by LC-MS/MS, whereas one-carbon metabolism enzyme expression was determined by RT-qPCR and western blotting. AutoDock Vina was employed to predict binding affinities of VPA to key metabolic enzymes.
KEY RESULTS: Na-VPA and its metabolites induced concentration- and time-dependent PAC death, independent of toxic calcium signalling. In vivo, Na-VPA aggravated CER-AP, increasing pancreatic histology scores and biochemical parameters. Transcriptomic and metabolomic analyses showed dysregulated one-carbon metabolism, validated by altered mRNA and protein expression analysis of key rate-limiting enzymes. Molecular docking indicated direct interactions between VPA and several metabolic enzymes. Na-VPA also activated the pancreatic endoplasmic reticulum (ER) stress pathway. In PACs, Na-VPA reduced methionine and S-adenosylmethionine (SAM) levels, whereas supplementation with methionine or SAM markedly attenuated cell injury; conversely, ethionine exacerbated it. Moreover, SAM supplementation in vivo significantly ameliorated pancreatic damage and biochemical alterations in Na-VPA-exacerbated CER-AP.
CONCLUSION AND IMPLICATIONS: Na-VPA disrupts one-carbon metabolism, triggering ER stress and acinar cell injury and exacerbating experimental pancreatitis. These findings provide new mechanistic insight into valproate-associated AP and identify metabolic targets for potential prevention or therapy.
EXPERIMENTAL APPROACH: Murine pancreatic acinar cells (PACs) were treated with Na-VPA or major VPA metabolites, and cytotoxicity was assessed by spectrofluorometry and confocal imaging. In vivo, C57BL/6 mice, with or without caerulein-induced pancreatitis (CER-AP), were administered Na-VPA and pancreatic injury was evaluated. Intracellular methionine-cycle metabolites were quantified by LC-MS/MS, whereas one-carbon metabolism enzyme expression was determined by RT-qPCR and western blotting. AutoDock Vina was employed to predict binding affinities of VPA to key metabolic enzymes.
KEY RESULTS: Na-VPA and its metabolites induced concentration- and time-dependent PAC death, independent of toxic calcium signalling. In vivo, Na-VPA aggravated CER-AP, increasing pancreatic histology scores and biochemical parameters. Transcriptomic and metabolomic analyses showed dysregulated one-carbon metabolism, validated by altered mRNA and protein expression analysis of key rate-limiting enzymes. Molecular docking indicated direct interactions between VPA and several metabolic enzymes. Na-VPA also activated the pancreatic endoplasmic reticulum (ER) stress pathway. In PACs, Na-VPA reduced methionine and S-adenosylmethionine (SAM) levels, whereas supplementation with methionine or SAM markedly attenuated cell injury; conversely, ethionine exacerbated it. Moreover, SAM supplementation in vivo significantly ameliorated pancreatic damage and biochemical alterations in Na-VPA-exacerbated CER-AP.
CONCLUSION AND IMPLICATIONS: Na-VPA disrupts one-carbon metabolism, triggering ER stress and acinar cell injury and exacerbating experimental pancreatitis. These findings provide new mechanistic insight into valproate-associated AP and identify metabolic targets for potential prevention or therapy.