Potential role of tryptophan metabolites in the sex-based differences in doxorubicin-induced chronic cardiotoxicity in a rat model

The clinical use of doxorubicin (DOXO) may be limited by its dose-dependent chronic cardiotoxicity, the severity of which shows sex-based differences. Several tryptophan (Trp) metabolites are associated with oxidative stress, inflammation, and metabolic disturbances in heart failure. Here, we aimed to characterize changes in left ventricular (LV) concentrations of selected Trp metabolites in DOXO-induced chronic cardiotoxicity in both sexes. Therefore, male and female Wistar rats (300-400 g) were divided into 2-2 groups: physiological saline-treated (i.p., 6x1 mL/kg) control and DOXO-treated (i.p., 6x1 mg/kg) groups. At weeks 12 and 19, echocardiography was performed. At week 20, blood pressure measurement, histology in LV and renal samples, RT-qPCR, and UHPLC-MS/MS for genes and metabolites related to oxidative stress, inflammation, glucose and fatty acid metabolism, and Trp metabolites in LV samples were performed. At week 12, diastolic dysfunction developed in both sexes. At the endpoint, DOXO-treated animals showed echocardiographic, histologic, and molecular signs of chronic cardiotoxicity, accompanied by LV repression of glycerol-3-phosphate dehydrogenase and carnitine palmitoyltransferase, overexpression of glucose transporter-1, increased levels of 3-hydroxykynurenine, and mild renal fibrosis without blood pressure elevation in both sexes. However, only male DOXO-treated rats exhibited systolic dysfunction, a lower reduced-to-oxidized glutathione ratio, overexpression of interleukin-6, increased levels of kynurenine, quinolinic acid, and glomerular hypertrophy. DOXO-treated females showed higher levels of anthranilic acid and overexpression of acyl-CoA dehydrogenase, suggesting better fatty acid utilization. In conclusion, male animals developed accelerated DOXO-induced chronic cardiotoxicity accompanied by more pronounced changes in the markers of oxidative stress, inflammation, and Trp metabolism.