Diabetes mellitus increases the in vivo activity of cytochrome P450 2E1 in humans
Diabetes mellitus increases the in vivo activity of cytochrome P450 2E1 in humans
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DOI：
10.1046/j.1365-2125.2003.01731.x
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发表时间：
2003-01-01
影响因子：
3.4
通讯作者：
Gorski, JC
中科院分区：
文献类型：
--
作者：
Wang, ZQ;Hall, SD;Gorski, JC
细胞色素P450 2 E1（CYP 2 E1）被认为激活了许多原毒素，并与肝脏疾病的发展有关。在糖尿病大鼠模型中，肝脏CYP 2 E1表达增加，但尚不清楚人类糖尿病患者是否显示类似的上调。本研究的目的是检验假设，人类糖尿病患者的经验增强CYP 2 E1 expression.Methods氯唑沙宗（500 mg），作为肝CYP 2 E1活性的指标，单剂量的药代动力学，在健康受试者（n = 10），志愿者与I型糖尿病（n = 13），和II型糖尿病（n = 8）。采用高效液相色谱法测定血清和尿液中氯唑沙宗和6-羟基氯唑沙宗的浓度。采用逆转录聚合酶链反应（RT-PCR）检测外周血单个核细胞CYP 2 E1 mRNA的表达。(90氯唑沙宗的血药浓度-时间曲线下面积与对照组相比差异有显著性（P <0.05）。肥胖II型糖尿病患者中（P ≤ 0.05）降低（15.7 +/- 11.3 mug h ml（-1）; 9，22）与健康受试者相比（43.5 +/- 16.9 mug h ml（-1）; 16，40）和I型糖尿病患者（32.8 +/- 9.2 mug h ml（-1）; 9，25）。与健康志愿者和I型糖尿病患者相比，肥胖II型糖尿病患者氯唑沙宗的口服清除率显著增加两倍。三组间氯唑沙宗的蛋白结合率无显著差异。相比之下，1型糖尿病患者和健康志愿者在氯唑沙宗的口服清除率方面没有差异。6-羟基氯唑沙宗的尿回收率占给药剂量的百分比在健康、I型和肥胖II型糖尿病患者之间没有差异。三组间氯唑沙宗的消除半衰期无差异。与健康志愿者相比，CYP 2 E1 mRNA在I型和肥胖II型糖尿病患者中显著升高。口服清除氯唑沙宗，消除半衰期，Tmax，和C-max没有显着影响体重，体重指数，血糖，血清胆固醇，或糖化血红蛋白。结论有一个显着增加肝脏CYP 2 E1活性肥胖II型糖尿病患者评估氯唑沙宗处置。两型糖尿病患者外周血单个核细胞CYP 2 E1 mRNA表达均增加。与II型糖尿病相关的肝脏不良事件可能部分是由于CYP 2 E1表达和活性增强所致。
Aims Cytochrome P450 2E1 (CYP2E1) is thought to activate a number of protoxins, and has been implicated in the development of liver disease. Increased hepatic expression of CYP2E1 occurs in rat models of diabetes but it is unclear whether human diabetics display a similar up-regulation. This study was designed to test the hypothesis that human diabetics experience enhanced CYP2E1 expression.Methods The pharmacokinetics of a single dose of chlorzoxazone (500 mg), used as an index of hepatic CYP2E1 activity, was determined in healthy subjects (n = 10), volunteers with Type I (n = 13), and Type II (n = 8) diabetes mellitus. Chlorzoxazone and 6-hydroxychlorzoxazone in serum and urine were analysed by high-performance liquid chromatography. The expression of CYP2E1 mRNA in peripheral blood mononuclear cells was quantified by reverse transcriptase-polymerase chain reaction.Results The mean +/- s.d. (90% confidence interval of the difference) chlorzoxazone area under the plasma concentration-time curve was significantly (P less than or equal to 0.05) reduced in obese Type II diabetics (15.7 +/- 11.3 mug h ml(-1) ; 9, 22) compared with healthy subjects (43.5 +/- 16.9 mug h ml(-1); 16, 40) and Type I diabetics (32.8 +/- 9.2 mug h ml(-1) ; 9, 25). There was a significant two-fold increase in the oral clearance of chlorzoxazone in obese Type II diabetics compared with healthy volunteers and Type I diabetics. The protein binding of chlorzoxazone was not significantly different between the three groups. In contrast, Type 1 diabetics and healthy volunteers demonstrated no difference in the oral clearance of chlorzoxazone. The urinary recovery of 6-hydroxychlorzoxazone as a percentage of the administered dose was not different between healthy, Type I and obese Type II diabetics. The elimination half-life of chlorzoxazone did not differ between the three groups. CYP2E1 mRNA was significantly elevated in Type I and obese Type II diabetics compared with healthy volunteers. The oral clearance of chlorzoxazone, elimination half-life, T-max, and C-max were not significantly influenced by weight, body mass index, serum glucose, serum cholesterol, or glycosylated haemoglobin.Conclusions There was a marked increase in hepatic CYP2E1 activity in obese Type II diabetics as assessed by chlorzoxazone disposition. Increased expression of CYP2E1 mRNA in peripheral blood mononuclear cells was found in both types of diabetes mellitus. Adverse hepatic events associated with Type II diabetes may be in part a result of enhanced CYP2E1 expression and activity.