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Modulation of Cytochrome P450-dependent Monooxygenases in Streptozotocin-induced Diabetic Hamster: II. Reverse Role of Insulin in P450 Activity and Defluorination

糖尿病倉鼠細胞色素P450單氧酵素之研究:Ⅱ、胰島素對於P450酵素活性及去氟化能力所扮演的角色

摘要


背景:動物體內負責藥物代謝之細胞色素P450酵素群,可被疾病狀態如糖尿病所調控,本研究以糖尿病倉鼠為模式,探討注射胰島素後,其肝、腎內微粒體酵素活性的改變,以及對吸入性麻醉劑去氟化代謝能力的影響。 方法:以streptozotocin40毫克/公斤體重的劑量,連續四天腹腔內注射,誘導形成糖尿病倉鼠(糖尿病組),待六週穩定後,再給予胰島素皮下注射一天兩次,以恢復其正常血糖(胰島素組),四週後取其肝、腎微粒體,與對照組比較細胞色素1A1,2B1,2EI及3A4之代謝活性,以及對enflurane去氟化代謝能力之差异,并分別以光譜分析、蛋白電泳及顯微鏡病理切片,測量其活性、酵素含量及顯微構造之變化,藉以評估胰島素治療之效應。 結果:糖尿病狀態可使細胞色素酵素2E1活性增加,并使enflurane去氟化程度上升,而酵素2B1活性則下降將近50%;至於酵素1A1及3A4則無明顯變化。蛋白質泳結果與活性變化大致相近,顯微鏡下病理結果則顯示肝細胞間質增加許多脂肪顆粒。以上變化在給予胰島素後皆回腹與控制組近似。 結論:在糖尿病倉鼠身上注射胰島素後,可在酵素蛋白活性、含量、電泳特性及病理變化等,以及吸入性麻醉藥劑去氟化能力上,回復接近控制組之正常狀態,此結果可提醒臨床醫師重視糖尿病患可能產生之藥物代謝變化,以及胰島素治療角色之重要性。

並列摘要


Background: Metabolic activities of cytochrome(cyt) P450-dependent monooxygenase could be modulated by diabetic state in experimental diabetic animals. The purpose of this study is to validate the effect of insulin on the modulation of the metabolic activity of cyt P450 and the defluorination ability to inhalational anesthetics in diabetic animals. Methods: Diabetic state in golden Syrian hamsters was achieved by intraperitoneal injection of streptozotocin 40 mg/kg once a day for 4 days. After stabilization of diabetic state for 6 weeks, a regimen of insulin treatment given subcutaneously was carried out. Metabolic activities of cyt P450 were assessed by the reaction with benzo(a) pyrene, pentoxyresorufin, aniline and erythromycin (specific substrates). The metabolic activities of cyt 1A1, 2B1, 2E1 and 3A4 respectively in a NADPH-generating system in microsomal preparations of the diabetic hamsters were observed before and after insulin treatment, and were compared with the control group. The ability of defluorination was evaluated by measuring the free fluoride metabolites after incubating the microsomes with enflurane in diabetic and insulin-treated hamsters. Contents of cyt P450 isozymes were measured by electrophoresis and immunoblotting before and after insulin treatment. Pathological features of hepatocytes in diabetic hamsters were evaluated microscopically before and after insulin treatment. Results: The defluorination of enflurane and activity of aniline hydroxylase (cyt 2E1) were successfully induced by diabetic state (P < 0.01). The pentoxyresorufin 0-dealkylase (cyt 2B1) was inhibited nearly 50% in the diabetic hamster liver when compared with that of control (P <0.01). While the activities of benzo(a)pyrene hydroxylase (cyt 1A1) and the erythromycin N-demethylase (cyt 3A4) were basically unaffected by diabetes, alterations in content of cyt P450 were parallel to the alterations in enzyme activities. Microscopically, diabetes induced vacuolization with fatty droplets in the hepatocytes. After treatment with insulin injection, the enzyme activities, protein content and pathologic features returned to the baseline similar to the control. Conclusions: Our data demonstrated that under diabetic state, metabolic activities of cyt P450 and its extent of defluorination would be polymorphically modulated. After administration of insulin, the activities of cyt P450 and defluorination of enflurane returned to baseline as the blood sugar level had been normalized. This could remind the clinicians of the importance of insulin treatment in the potential drug-to-drug interactions in the diabetic patients.

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