ABSTRACT
This study demonstrates that aspartame consumption and insulin treatment in a juvenile diabetic rat model leads to increase in cytochrome P450 (CYP) 2E1 and CYP3A2 isozymes in brain. Diabetes mellitus was induced in postweaned 21-day-old Wistar male rat by streptozotocin. Animals were randomly assigned to one of the following groups: untreated control, diabetic (D), D-insulin, D-aspartame, or the D-insulin + aspartame-treated group. Brain and liver tissue samples were used to analyze the activity of CYP2E1 and CYP3A2 and protein levels. Our results indicate that combined treatment with insulin and aspartame in juvenile diabetic rats significantly induced CYP2E1 in the cerebrum and cerebellum without modifying it in the liver, while CYP3A2 protein activity increased both in the brain and in the liver. The induction of CYP2E1 in the brain could have important in situ toxicological effects, given that this CYP isoform is capable of bioactivating various toxic substances. Additionally, CYP3A2 induction in the liver and brain could be considered a decisive factor in the variation of drug response and toxicity.
Subject(s)
Aspartame/therapeutic use , Cerebellum/enzymology , Cerebrum/enzymology , Cytochrome P-450 CYP2E1/metabolism , Cytochrome P-450 CYP3A/metabolism , Diabetes Mellitus, Type 1/diet therapy , Non-Nutritive Sweeteners/therapeutic use , Animals , Aspartame/adverse effects , Cerebellum/drug effects , Cerebrum/drug effects , Combined Modality Therapy/adverse effects , Cytochrome P-450 CYP2E1/chemistry , Cytochrome P-450 CYP2E1 Inducers/adverse effects , Cytochrome P-450 CYP2E1 Inducers/therapeutic use , Cytochrome P-450 CYP3A/chemistry , Cytochrome P-450 CYP3A Inducers/adverse effects , Cytochrome P-450 CYP3A Inducers/therapeutic use , Diabetes Mellitus, Type 1/blood , Diabetes Mellitus, Type 1/drug therapy , Diabetes Mellitus, Type 1/metabolism , Enzyme Induction/drug effects , Hyperglycemia/prevention & control , Hypoglycemic Agents/adverse effects , Hypoglycemic Agents/therapeutic use , Insulin/adverse effects , Insulin/therapeutic use , Liver/drug effects , Liver/enzymology , Male , Nerve Tissue Proteins/agonists , Nerve Tissue Proteins/metabolism , Neurons/drug effects , Neurons/enzymology , Non-Nutritive Sweeteners/adverse effects , Organ Specificity , Random Allocation , Rats, WistarABSTRACT
The effect of transfluthrin (TF) or D-allethrin (DA) pyrethroid (PYR) vapors, often contained as main ingredients in two commercially available mosquito repellent mats, on cytochrome P450 (CYP) enzymes of rat brain and liver was assessed. Immunodetection of CYP2E1 and CYP3A2 proteins revealed their induction in cerebrum and cerebellum, but not in liver microsomes of rats exposed by inhalation to TF or DA. This overexpression of proteins correlated with an increase of their catalytic activities. The specifically increased expression of CYP isoenzymes, due to PYR exposure in the rat brain, could perturb the normal metabolism of endogenous and xenobiotic compounds and leads to increased risks of neurotoxicity by bioactivation, lipid peroxidation and DNA damage.
Subject(s)
Brain/drug effects , Cytochrome P-450 Enzyme System/metabolism , Insecticide-Treated Bednets , Insecticides/toxicity , Pyrethrins/toxicity , Allethrins/chemistry , Allethrins/toxicity , Animals , Blotting, Western , Brain/enzymology , Cyclopropanes/chemistry , Cyclopropanes/toxicity , Cytochrome P-450 CYP2E1/metabolism , Cytochrome P-450 CYP3A/metabolism , Electrophoresis, Polyacrylamide Gel , Fluorobenzenes/chemistry , Fluorobenzenes/toxicity , Inhalation Exposure , Insecticide-Treated Bednets/adverse effects , Insecticides/chemistry , Lipid Peroxidation/drug effects , Liver/drug effects , Liver/enzymology , Male , Membrane Proteins/metabolism , Microsomes/drug effects , Microsomes/enzymology , Neurotoxicity Syndromes/enzymology , Neurotoxicity Syndromes/etiology , Pyrethrins/chemistry , Rats , Rats, Wistar , VolatilizationABSTRACT
Gastrointestinal tissues are directly exposed to dietary xenobiotics. In spite of this, modulation of cytochrome P450 (CYP) enzymes in the gastrointestinal tract is not well established. CYP induction could facilitate transformation of chemical agents to potentially toxic or carcinogenic metabolites. This might also determine drug efficacy, burden of foreign chemicals on tissues or bioavailability of certain therapeutic agents. In order to assess the induction of the CYP subfamilies 1A1/2, 2B1/2, 2E1 and 3A2 in the gastrointestinal tract, male Wistar rats were treated with phenobarbital/ß-naphthoflavone (PB/NF), cyclohexanol/albendazole (CH/ABZ) or toluene (TL). Microsomal fractions were prepared from tissue samples of the esophagus, the stomach, the duodenum, the colon and the liver. Western blot and enzymatic activity analyses revealed an increase in the expression and activity of CYP1A1/2 and CYP3A2 isoenzymes in the esophageal, duodenal and colonic microsomes from animals treated with PB/NF. CYP1A1/2 and CYP3A2 were induced in hepatic and duodenum microsomes by treatment with CH/ABZ. Our results demonstrate differential induction of CYP along the gastrointestinal tract by known CYP hepatic inducers, being the treatment with PB/NF the best induction system of the CYPs.
