Dual mass spectrometry imaging and spatial metabolomics to investigate the metabolism and nephrotoxicity of nitidine chloride

Yang Shu; Wang Zhonghua; Liu Yanhua; Zhang Xin; Zhang Hang; Wang Zhaoying; Zhou Zhi; Abliz Zeper

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Dual mass spectrometry imaging and spatial metabolomics to investigate the metabolism and nephrotoxicity of nitidine chloride

Author: Yang SHU ¹ ; Wang ZHONGHUA ; Liu YANHUA ; Zhang XIN ; Zhang HANG ; Wang ZHAOYING ; Zhou ZHI ; Abliz ZEPER
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1. School of Pharmacy,Minzu University of China,Beijing,100081,China
Keywords: Nitidine chloride; Nephrotoxicity; Mass spectrometry imaging; Spatial metabolomics; Toxicokinetics
From: Journal of Pharmaceutical Analysis 2024;14(7):1011-1023
CountryChina
Language:Chinese
Abstract: Evaluating toxicity and decoding the underlying mechanisms of active compounds are crucial for drug development.In this study,we present an innovative,integrated approach that combines air flow-assisted desorption electrospray ionization mass spectrometry imaging(AFADESI-MSI),time-of-flight secondary ion mass spectrometry(ToF-SIMS),and spatial metabolomics to comprehensively investi-gate the nephrotoxicity and underlying mechanisms of nitidine chloride(NC),a promising anti-tumor drug candidate.Our quantitive AFADESI-MSI analysis unveiled the region specific of accumulation of NC in the kidney,particularly within the inner cortex(IC)region,following single and repeated dose of NC.High spatial resolution ToF-SIMS analysis further allowed us to precisely map the localization of NC within the renal tubule.Employing spatial metabolomics based on AFADESI-MSI,we identified over 70 discriminating endogenous metabolites associated with chronic NC exposure.These findings suggest the renal tubule as the primary target of NC toxicity and implicate renal transporters(organic cation transporters,multidrug and toxin extrusion,and organic cation transporter 2(OCT2)),metabolic en-zymes(protein arginine N-methyltransferase(PRMT)and nitric oxide synthase),mitochondria,oxidative stress,and inflammation in NC-induced nephrotoxicity.This study offers novel insights into NC-induced renal damage,representing a crucial step towards devising strategies to mitigate renal damage caused by this compound.