Wang Bing, He Fan, Lin Yu, Huang Min, Zhou Shu-Feng
Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510080, China.
Drug Metab Lett. 2007 Aug;1(3):199-204. doi: 10.2174/187231207781369825.
There is an increasing application of protein/peptide drugs in the treatment of various diseases such as cancer and autoimmune diseases in clinical settings. However, data is scant on the potential for modulation of cytochrome P450s (CYPs) by these protein/peptide drugs. In this study, we examined the effects of recombinant human thymosin-alpha1 (rh-T alpha 1) on hepatic cytochrome P450 (CYP) enzyme activity in rats in vitro and in vivo. For the in vitro experiments, rh-T alpha 1 was incubated with the probe drugs and the liver microsomes from rats, while rh-T alpha 1 was administered to rats subcutaneously at 150, 300, or 600 microg/kg daily for two weeks in in vivo studies. The activities of six rat hepatic CYP enzymes, namely CYP1A2, CYP2C6, CYP2C11, CYP2D2, CYP2E1, and CYP3A1/2, were determined by a cocktail of probe drugs including phenacetin (O-deethylation), tolbutamide (4-hydrolylation), omeprazole (5-hydroxylation), dextromethorphan (O-demethylation), chlorzoxazone (6-hydroxylation), and nifedipine (N-dehydrogenation), respectively. Co-incubation of rh-T alpha(1) at the concentration of 20 and 50 micromol/l with the liver microsomes significantly inhibited CYP2E1 activity, whereas there was no significant effect on the activities of CYP1A2, CYP2C6, CYP2C11, CYP2D2, and CYP3A1/2. As to in vivo studies, treatment of rh-T alpha 1 at either dosage did not significantly alter the liver weight. However, an ex vivo study demonstrated that the activity of rat hepatic CYP2E1 was significantly increased by pretreatment of rh-T alpha 1 at the three doses for two weeks, and the activities of CYP1A2, CYP2D2, and CYP3A1/2 were also significantly increased in rats pretreated with rh-T alpha 1 at 600 microg/kg. These data indicate that rh-T alpha 1 can modulate the activities of major rat CYP isoforms, and further studies are needed to investigate its effect on human CYP activities and the potential for causing drug interactions.
在临床环境中，蛋白质/肽类药物在治疗各种疾病（如癌症和自身免疫性疾病）中的应用日益增加。然而，关于这些蛋白质/肽类药物对细胞色素P450（CYP）的调节潜力的数据却很少。在本研究中，我们在体外和体内研究了重组人胸腺素α1（rh-Tα1）对大鼠肝细胞色素P450（CYP）酶活性的影响。在体外实验中，将rh-Tα1与探针药物和大鼠肝脏微粒体一起孵育，而在体内研究中，rh-Tα1以150、300或600μg/kg的剂量每日皮下注射给大鼠，持续两周。分别通过包括非那西丁（O-脱乙基）、甲苯磺丁脲（4-羟基化）、奥美拉唑（5-羟基化）、右美沙芬（O-去甲基）、氯唑沙宗（6-羟基化）和硝苯地平（N-脱氢）的探针药物混合物来测定六种大鼠肝脏CYP酶，即CYP1A2、CYP2C6、CYP2C11、CYP2D2、CYP2E1和CYP3A1/2的活性。rh-Tα1以20和50μmol/l的浓度与肝脏微粒体共同孵育显著抑制了CYP2E1的活性，而对CYP1A2、CYP2C6、CYP2C11、CYP2D2和CYP3A1/2的活性没有显著影响。至于体内研究，两种剂量的rh-Tα1治疗均未显著改变肝脏重量。然而，一项体外研究表明，三种剂量的rh-Tα1预处理两周后，大鼠肝脏CYP2E1的活性显著增加，并且在以600μg/kg的rh-Tα1预处理的大鼠中，CYP1A2、CYP2D2和CYP3A1/2的活性也显著增加。这些数据表明rh-Tα1可以调节大鼠主要CYP同工型的活性，需要进一步研究来调查其对人CYP活性的影响以及引起药物相互作用的可能性。
