Boldine activates Nrf2/ARE signaling to alleviate 5-fluorouracil-induced apoptosis, oxidative stress and inflammation in liver tissue of rats.

Abstract

5-Fluorouracil (5-FU) is widely used in the treatment of various solid tumors; however, its clinical use is often limited by hepatotoxicity. Boldine, an aporphine alkaloid, has been reported to possess antioxidant, anti-inflammatory, and hepatoprotective properties. The present study evaluated the hepatoprotective potential of boldine against 5-FU-induced liver injury in Wistar rats. Hepatotoxicity was induced by a single intraperitoneal injection of 5-FU (150 mg/kg). Following 5-FU administration, rats were orally treated with boldine (10 or 20 mg/kg body weight) or the standard hepatoprotective agent silymarin (100 mg/kg body weight) once daily for 7 days. At the end of the experimental period, serum transaminases, oxidative stress markers, antioxidant status, and hepatic gene expression related to oxidative stress and inflammation were evaluated using PCR analysis. Administration of 5-FU was associated with increased serum transaminases and oxidative stress markers, consistent with hepatocellular injury. In addition, 5-FU exposure was accompanied by reduced mRNA expression of antioxidant-related genes (Nrf2, NQO1, and HO-1) and increased expression of CUL3 and inflammatory/apoptosis-related markers (ASK1, ERK1, and NF-κB), along with decreased Bcl-2 expression. Boldine treatment significantly attenuated biochemical and molecular alterations, enhanced dihydropyrimidine dehydrogenase expression involved in 5-FU metabolism, and ameliorated histopathological changes. Overall, these findings suggest that boldine may exert hepatoprotective effects against 5-FU-induced liver injury, potentially through modulation of oxidative stress and inflammatory pathways.

Key Findings

• Boldine activates Nrf2/ARE signaling pathway to counteract 5-FU-induced oxidative stress and inflammation in rat liver tissue.
• 5-FU administration increases serum transaminases and oxidative stress markers, decreases antioxidant gene expression (Nrf2, NQO1, HO-1), and increases inflammatory/apoptosis markers.
• Boldine treatment attenuates biochemical and molecular liver injury markers, enhances 5-FU metabolism enzyme expression, and improves histopathological liver changes.

Clinical Significance

Citation

Divya Dharshini Kalangiyam, Sharmila Muthusethupathi, Munusamy Karthicket al.. Boldine activates Nrf2/ARE signaling to alleviate 5-fluorouracil-induced apoptosis, oxidative stress and inflammation in liver tissue of rats. Drug and chemical toxicology. 2026-Mar-29.