Chemical Profiling of Citrus sinensis Root and the Effects of Its Secondary Metabolites on Cisplatin-Induced Renal and Cardiac Toxicities

Abstract

Citrus fruits are among the most important economical crops, because of their nutritional value, medicinal importance, and unique flavor. Gas liquid chromatography-mass spectrometry of the hydro-distilled oil from the root resulted in the identification of 110 compounds with germacrene B (22%), aromadendrene (21.6%), α-santalene (7.1%), geijerene (4,81%), germacrene D (4.3%), and limonene (3.4%) as major constituents. In addition, chemical profiling the dichloromethane fraction of the root analyzed by high-performance liquid chromatography-photo diode array detector-electrospray tandem mass spectrometry afforded the identification of 43 compounds belonging to acridone alkaloids, coumarins, and flavonoids. Moreover, xanthyletin, citracridone I and II, clausarin, O-methylcitrusinine-I, and grandisinine were isolated as major metabolites using column chromatography and characterized depending on different spectroscopic techniques. Xanthyletin and citracridone I were investigated for their in vitro cytotoxicity against hepatocellular carcinoma and breast adenocarcinoma cell lines, and in vivo protective effect against cisplatin-induced nephrotoxicity and cardiotoxicity in different dose levels in a rat model. Xanthyletin and citracridone I showed protective activity against cisplatin-induced nephrotoxicity. It attenuated cisplatin-induced elevation of both serum urea and creatinine in a dose-dependent manner. Moreover, xanthyletin attenuated cisplatin-induced elevation of malondialdehyde and glutathione in both renal and cardiac tissues. Graphical abstract: [Figure not available: see fulltext.]