Nanoencapsulated Curcumin Mitigates Liver Injury and Drug-Metabolizing Enzymes Induction in Diclofenac-Treated Mice.

Curcumin (CUR) is a natural product with known anti-inflammatory, antioxidant, and hepatoprotective properties. The aim of this study was to formulate CUR into a polymeric nanoparticle (NP) formulation and examine its potential hepatoprotective activity in an animal model of diclofenac (DIC)-induced hepatotoxicity. CUR was loaded into polymeric NPs composed of poly(ethylene glycol)-polycaprolactone (PEG-PCL). The optimal CUR NPs were evaluated against DIC-induced hepatotoxicity in mice, by studying the histopathological changes and gene expression of drug-metabolizing cyp450 (cyp2c29 and cyp2d9) and ugt (ugt2b1) genes in the livers of the animals. The optimal NPs were around 67 nm in diameter with more than 80% loading efficiency and sustained release. Histological findings of mice livers revealed that CUR NPs exhibited a superior hepatoprotective effect compared to free CUR, and both groups reduced DIC-mediated liver tissue injury. While treatment with DIC alone or with CUR and CUR NPs had no effect on cyp2c29 gene expression, cyp2d9 and ugt2b1 genes were upregulated in the DIC-treated group, and this effect was reversed by CUR both as a free drug and as CUR NPs. Our findings present a promising application for nanoencapsulated CUR in the treatment of nonsteroidal anti-inflammatory drugs-induced liver injury and the associated dysregulation in the expression of hepatic drug-metabolizing enzymes.

Relative Expression of Mouse Udp-glucuronosyl Transferase 2b1 Gene in the Livers, Kidneys, and Hearts: The Influence of Nonsteroidal Anti-inflammatory Drug Treatment.

BACKGROUND: Mouse Udp-glucuronosyl Transferase (UGT) 2b1 is equivalent to the human UGT2B7 enzyme, which is a phase II drug-metabolising enzyme and plays a major role in the metabolism of xenobiotic and endogenous compounds. This study aimed to find the relative expression of the mouse ugt2b1 gene in the liver, kidney, and heart organs and the influence of Nonsteroidal Anti-inflammatory Drug (NSAID) administration. METHODS: Thirty-five Blab/c mice were divided into 5 groups and treated with different commonly-used NSAIDs; diclofenac, ibuprofen, meloxicam, and mefenamic acid for 14 days. The livers, kidneys, and hearts were isolated, while the expression of ugt2b1 gene was analysed with a quantitative real-time polymerase chain reaction technique. RESULTS: It was found that the ugt2b1 gene is highly expressed in the liver, and then in the heart and the kidneys. NSAIDs significantly upregulated (ANOVA, p < 0.05) the expression of ugt2b1 in the heart, while they downregulated its expression (ANOVA, p < 0.05) in the liver and kidneys. The level of NSAIDs' effect on ugt2b1 gene expression was strongly correlated (Spearman's Rho correlation, p < 0.05) with NSAID's lipophilicity in the liver and its elimination half-life in the heart. CONCLUSION: This study concluded that the mouse ugt2b1 gene was mainly expressed in the liver, as 14-day administration of different NSAIDs caused alterations in the expression of this gene, which may influence the metabolism of xenobiotic and endogenous compounds.

Effects of nonsteroidal anti-inflammatory drugs on the expression of arachidonic acid-metabolizing Cyp450 genes in mouse hearts, kidneys and livers.

Arachidonic acid (ARA) metabolites are involved in cardiovascular diseases and drug-induced cardiotoxicity. The present study aimed to investigate the effects of nonsteroidal anti-inflammatory drugs (NSAIDs) on the gene expression of ARA-metabolizing cyp450 genes in the hearts, kidneys and livers of experimental mice. Thirty five Balb/c mice were divided into 5 groups, and each group contained 7 mice. Then, the groups were administered different NSAIDs, diclofenac mefenamic acid, ibuprofen, or meloxicam, for 14 days in doses equivalent to those used in human treatment. Subsequently, liver, kidney and heart samples were isolated for analysis of the expression of ARA-metabolizing cyp450 genes using real-time polymerase chain reaction. In addition, the histological alterations induced by mefenamic acid were examined. It was found that 20-HETE synthesizing gene cyp4a12 was upregulated (> 2.2 fold) in the hearts of NSAID-treated mice, which was associated with the 2-fold downregulation of the cardio-protective biomarker GATA4 gene and the induction of cox2 expression (p value < 0.05). In the kidneys, the expression of cyp4a12 was significantly reduced (p value <0.05) while cyp2c29 expression was upregulated by more than 2 fold. In the liver, all NSAIDs except diclofenac significantly decreased the expression of all genes tested (p value <0.05) and were associated with abnormal accumulation of fat in the liver. Furthermore, these molecular findings were in parallel to histological alterations induced in the liver, kidney, and heart after mefenamic acid administration. This study concluded that NSAIDs altered the expression of ARA-metabolizing cyp450 genes and induced histological alterations that may influence the function of the vital organs.