Abstract
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.
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