Cytochrome P450 dependent drug metabolism in diabetic rabbits

Arslan, Şevki
Diabetus mellitus is a metabolic disorder of carbohydrate, fat and protein metabolism as a result of insulin deficiency or diminished tissue response to insulin. In this study, diabetes was induced in rabbits experimentally by intravenous injection of 100mg/kg alloxan. Injection of a single dose of alloxan to rabbits induced diabetus mellitus as it was understood from 4-fold increase in the blood glucose level and also 2-fold increase in blood urea concentrations. The influence of diabetus mellitus on cytochrome P450 levels, microsomal cytochrome P450 dependent drug metabolizing enzymes and on the biomarkers used to measure chemical-induced toxicity including AST, ALT and LDH were examined in rabbit liver, kidney and lung.Results obtained in this study showed that diabetus mellitus elevated microsomal cytochrome P450 contents of liver and kidney by 1.3- and 2-fold, respectively. Induction of the cytochrome P450 isozymes was observed with the high intensity bands having Mr between 51 000 Da and 53 000 Da and 45 000 Da to 48 000 Da in the SDS-PAGE profiles of liver microsomes obtained from the diabetic rabbits. However, the changes in kidney and lung microsomal protein patterns of diabetic rabbits compared to control animals were not so pronounced as observed in rabbit liver. Induction of diabetus mellitus caused 1.67-, 2.36- and 1.32-fold increases in aniline 4-hydroxylation rates of liver, kidney and lung microsomes, respectively. Induction of experimental diabetes enhanced hydroxylation rates of /Miitrophenol by liver, kidney and lung microsomes about 1.8-, 2.3- and 1.32-fold, respectively. NDMA N- demethylase activity was enhanced by diabetes in all three of these organs. (1.98-fold in liver, 1.85-fold in kidney, 1.35-fold in lung). Induction of diabetes in rabbits caused an increase of the P4502E1 level of microsomes and this was reflected in increased rate of metabolism of aniline, p-nitrophenol and NDMA. In this study, blood serum triglyceride, creatinine, urea and cholesterol concentrations were determined in control and diabetic rabbits. In addition, the effects of diabetes on transaminases (ALT and AST) and lactate dehydrogenase enzyme activities of rabbit blood serum and soluble fractions of rabbit liver, kidney and lung were investigated. Histological studies were carried out in control and diabetic rabbit liver and kidney tissue samples to investigate any tissue degeneration (necrosis). This is the first time induction of cytochrome P450 dependent monooxygenases has been reported for liver, kidney and lung microsomes of diabetic rabbits.


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Citation Formats
Ş. Arslan, “Cytochrome P450 dependent drug metabolism in diabetic rabbits,” M.S. - Master of Science, Middle East Technical University, 2003.