Modulation of Cytochrome P-450 Dependent Monooxygenases in Streptozotocin-Induced Diabetic Hamster: I. Effects of Propofol on Defluorination and Cytochrome P-450 Activities

糖尿病倉鼠細胞色素P-450單氧酵素之研究：I.Propofol對於去氟化能力及P-450活性的影響

陳大樑(Ta-Liang Chen) ； 張懷嘉(Huai-Chia Chang) ； 陳廷貴(Tyng-Guey Chen) ； 戴裕庭(Yu-Tint Tai) ； 陳瑞明(Ruei-Ming Chen)

《Acta Anaesthesiologica Sinica》 38卷1期 (2000/03) Pp. 15-21

https://doi.org/10.6955/AAS.200003.0015

摘要

背景：糖尿病狀態可引起動物休全身性及代謝性的變化，本實驗即在探討以streptozotocin誘導倉鼠糖尿病狀態時，其體內單氧酵素系統與麻醉藥物的關系。
方法：本研究以streptozotocin 40毫克/公觔的劑量連續4天注射倉鼠腹腔內，6週後觀察尿值以評估是否完成糖尿病之誘導，並以代謝受質之特異性，分別測量倉鼠肝、腎內單氧酵素含量及活性之變化。進一步以試管內方式，觀察propofol對於糖尿病倉鼠肝、腎徵粒體中各種酵素，包括1A1，2B1，2E1及3A4之影響，同時亦以評估糖尿病狀態下對於吸入性麻醉劑enfluran代謝性雲氟化能力，受propofol影響之程度。
結果：propofol對於糖尿病倉鼠各種細胞色素産生不同程度之影響，尤以1A1，2B1抑制最明顯，2E1次之，而3A4則無明顯變化，至於去氟化能力之抑制，在低濃度propofol 0.05mM下，即産生明顯抑制，且抑制程度與propofol濃度呈正比現象。
結論：因此本研究顯示糖尿病狀態之生物體，對於各種外來物之代謝，會受到propofol不同程度的抑制，在臨床藥物動力學及藥物使用上，應予以重視。

關鍵字

實驗性糖尿病 ； Streptozotocin ； Propofol ； 細胞色素P-450 ； 肝腎臓徵粒體

並列摘要

Background: Diabetes mellitus could induce polymorphic alterations of metabolic activities of cytochrome P-450 dependent monooxygenases in chemical-induced diabetic animals. The purpose of this study is to define the functional impact of clinical concentrations of propofol on the metabolic activities of cytochrome P-450 in the diabetic animals.
Methods: In order to validate the effect of propofol on cytochrome P-450 activities, especially the cytochrome P-450 2E1 and its defluorination activity, we applied NADPH-generating system to measure the metabolizing activities of cytochrome P-450 isozymes of streptozotocin-induced diabetic hamsters within the microsomes preincubated with various concentrations of propofoL The extent of defluorination and activity of cytochrome P-450 2E1 were assessed by reacting the propofol-treated microsomes in NADPH-generating system with enflurane and aniline as substrates respectively. Drug metabolizing activities of cytochrome 1A1, 2B1, and 3A4 were evaluated by metabolizing specific substrates, benzo(a)pyrene, pentoxyresorufin and erythromycin, within the microsomes of diabetic hamsters preincubated with various concentrations of propofol.
Results: The hepatic and renal defluorination of enflurane was significantly inhibited by 0.05 and 0.10 mM propofol in the microsomes of diabetic hamster (P＜0.05). The activities of aniline hydroxylase (cytochrome 2E1), pentoxyresorufin O-dealkylase (cytochrome 2B1) and benzo(a)pyrene hydroxylase (cytochrome 1A1) were inhibited by propofol in a concentration-dependent manner from 0.05 to 0.10 mM. Howevet; propofol showed no significant effect to the erythromycin N-demethylase (cytochrome 3A4) at its concentration of 0.05-0.10 mM in the diabetic hamsters.
Conclusions: Our data demonstrated that propofol in therapeutic concentrations of 0.05 and 0.10 mM, could inhibit both liver and kidney defluorination and cytochrome P-450’s activities of the diabetic hamsters in vitro of different extent. This should remind clinicians of propofol’s potential drug-to-drug interactions in the diabetic patients.

並列關鍵字

Diabetes Mellitus, experimental ； Streptozotocin ； Propofol ； Cytochrome P-450 ； Microsomes: liver, kidney