The Effects of Apilarnil and Imatinib on GR/GST/TrxR1 Enzyme Activities and Pentose Phosphate Pathway Enzymes in Rats

Apilarnil, a relatively understudied bee-derived product from drone larvae, has recently gained attention due to its diverse chemical content and biological activities. Imatinib, a selective tyrosine kinase inhibitor widely used in cancer treatment, is recognized for its effectiveness but is also associated with off-target toxicities including disturbances in redox homeostasis. While previous studies have mainly focused on the roles of the key antioxidant enzymes glucose-6-phosphate dehydrogenase (G6PD), 6-phosphogluconate dehydrogenase (6PGD), glutathione reductase (GR), glutathione-S transferase (GST) and thioredoxin reductase (TrxR1) in tumor resistance mechanisms, their inhibition in non-cancerous cells may contribute systemic toxicity. This study investigated whether co-administration of apilarnil could alleviate the inhibitory effects of imatinib on these enzymes in vivo. The secondary metabolite profile of apilarnil was characterized using liquid chromatography-high resolution mass spectrometry (LC-HRMS) revealing a richness in phenolic compounds, notably isorhamnetin, phenolidzin, ascorbic acid, liquiritigenin, leucoside, 3-(4-hydroxyphenyl) propionic acid and caffeic acid. Enzyme activity assays showed that imatinib significantly suppressed the activities of G6PD, 6PGD, GR, GST and TrxR1 compared to the control group. However, co-treatment with apilarnil particularly at a dose of 400 mg/kg, markedly restored activities of these enzymes. Furthermore, molecular docking analysis was performed to assess the binding affinities and interaction profiles of imatinib with target enzymes, confirming its potent inhibitory potential and revealing distinct but comparable binding interactions. These findings suggest that apilarnil may exert a protective effect against imatinib-induced toxicity by modulating disruptions in metabolic enzyme activities.