Diabetes, Metabolic Syndrome and Obesity (Sep 2018)
Alterations in the gene expression of drug and arachidonic acid-metabolizing Cyp450 in the livers of controlled and uncontrolled insulin-dependent diabetic mice
Abstract
Yazun Bashir Jarrar, Luay Al-Essa, Abdulhasib Kilani, Mariam Hasan, Walid Al-Qerem Department of Pharmacy, College of Pharmacy, Al-Zaytoonah University of Jordan, Airport street, Amman, Jordan Background: Diabetic patients have lower capacity to metabolize drugs in comparison to normal people. Therefore, the present study aimed to investigate the alterations in gene expression of drug and arachidonic acid metabolizing cytochrome p450s (cyp450s) in the livers of controlled (CDM) and uncontrolled (UDM) insulin-dependent diabetic mice. Methods: Balb/c mice were treated with single dose of streptozocin (240 mg/kg) to induce diabetes and compared with control group, which was treated with citric buffer (pH =4.5). After 3 days, the blood glucose level was measured to confirm the induction of diabetes. Normalization of blood glucose level in diabetic mice was achieved after 0.1 mL/kg Mixtard® insulin therapy for more 5 days. Then, the mice livers were isolated to extract RNA and convert it to cDNA. The gene expression of 14 genes, which play a major role in drug and arachidonic acid metabolism, were measured using quantitative real-time polymerase chain reaction technique. Results: It was found that the gene expression was downregulated (ANOVA test, P-value <0.05) in the livers of UDM mice. The most downregulated genes were cyp4a12, cyp1a2, and slc22a1 with more than 10-fold reduction. The livers of CDM mice showed significantly (P-value <0.05) higher levels of mRNA than UDM mice, but still lower than the non-diabetic mice. Conclusion: This study concluded that hepatic gene expression of drug metabolizing and arachidonic acid- cyp450 enzymes is reduced in insulin-dependent diabetic mice, which can explain, at least in part, the variation in drug and fatty acid metabolism between normal and diabetic patients. Keywords: drug metabolism, gene expression, diabetes, insulin, arachidonic acid, CYP450s, UGTs
