Letrozole (LTZ) is a non-steroidal aromatase inhibitor that is commonly used in breast cancer therapy. It has several side effects that might lead to the drug's cessation and data of LTZ's potential adverse effects on the hepatorenal microenvironment was conflicting. In addition, searching for therapeutic interventions that could modulate its adverse effects will be very beneficial. So, this study aims to determine the impact of LTZ on the hepatorenal microenvironment in cyclic female rats with a proposed regulatory role of L-Carnitine (LC) supplementation giving molecular insights into its possible mechanism of action. LTZ (1 mg/kg using 0.5% carboxy methyl cellulose as a vehicle for 21 consecutive days orally) to assess its impact on hepatorenal microenvironment. After treatment with LC (100 mg/kg orally) for 14 days, hepatorenal redox state (lipid peroxides (MDA), reduced glutathione (GSH) and catalase enzyme (CAT)), as well as relative gene expression of nuclear factor erythroid 2-related factor 2 (Nrf-2), cytochrome-c (Cyt c) and caspase-3 (CASP-3) were evaluated. Histopathological examination and immunohistochemical staining of CASP-3 in both liver and kidney were done. LTZ altered hepatic and renal functions. Relative gene expression of hepatorenal Nrf-2, Cyt c and CASP-3 as well as redox state revealed significant deterioration. Also, the liver and kidney tissues showed several micromorphological changes and intense reaction to CASP-3 upon immunohistochemical staining. It can be concluded that LC alleviates LTZ induced hepatorenal oxidative stress (OS) and mitochondrial-dependent apoptotic progression through modulation of Nrf-2, Cyt c, and CASP-3 signaling in female rats.

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