Yeung John H K, Chan Siu-Lung, Or Penelope M Y
Department of Pharmacology, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, NT, Hong Kong, China.
Food Chem Toxicol. 2006 Aug;44(8):1414-23. doi: 10.1016/j.fct.2006.03.007. Epub 2006 Apr 25.
Polysaccharide peptide (PSP), isolated from COV-1 strain of Coriolus versicolor, is commonly used as an adjunct in cancer chemotherapy in China. In this study, the effects of whole PSP extract and water extract of PSP on 4-hydroxylation of tolbutamide were investigated in rat liver microsomes in vitro and in vivo in the rat. Both the whole PSP extract and the water soluble fraction (0.5-20 microM) decreased the metabolism of tolbutamide to 4-hydroxytolbutamide in vitro. Enzyme kinetics studies showed that PSP inhibited tolbutamide 4-hydroxylase activity in a competitive, concentration-dependent manner. The whole PSP extract had a Ki value of 12.6 microM and IC50 at 18.4 microM, while the water extract had a Ki value of 6.9 microM and IC50 at 9.8 microM. Sulphaphenazole, a specific human CYP2C9 inhibitor, showed a Ki value of 30.8 microM and IC50 at 44.0 microM in the test system. In the pharmacokinetic studies in vivo, acute PSP (4 micromol/kg, i.p.) treatment did not produce significant changes in tolbutamide clearance, but produced a decrease in the Cinitial (7.4%) and an increase in the Vd (7.4%). Sub-chronic pre-treatment of PSP (1-2 micromol/kg/day, i.p.) for three days did not affect the clearance and AUC of tolbutamide, but the Cinitial was decreased, together with increases in the T1/2, and Vd. The formation of 4-hydroxytolbutamide in vivo was decreased in both acute and sub-chronic studies. Taken together, this study demonstrated the PSP can inhibit tolbutamide 4-hydroxylation both in vitro and in vivo. Despite the fact that CYP isoforms that metabolise tolbutamide are different between rat and human liver due to different catalytic characteristics, and rat studies may not be directly extrapolatable to man, the concomitant use of PSP with other CYP2C substrates should be carefully monitored.
云芝多糖肽（PSP）是从云芝COV-1菌株中分离得到的，在中国常用于癌症化疗的辅助治疗。在本研究中，在大鼠肝微粒体中体外和体内研究了PSP全提取物和PSP水提取物对甲苯磺丁脲4-羟化的影响。PSP全提取物和水溶性部分（0.5 - 20 microM）在体外均降低了甲苯磺丁脲向4-羟基甲苯磺丁脲的代谢。酶动力学研究表明，PSP以竞争性、浓度依赖性方式抑制甲苯磺丁脲4-羟化酶活性。PSP全提取物的Ki值为12.6 microM，IC50为18.4 microM，而水提取物的Ki值为6.9 microM，IC50为9.8 microM。磺胺苯吡唑是一种特异性人CYP2C9抑制剂，在测试系统中的Ki值为30.8 microM，IC50为44.0 microM。在体内药代动力学研究中，急性给予PSP（4 micromol/kg，腹腔注射）未使甲苯磺丁脲清除率产生显著变化，但使Cinitial降低（7.4%），Vd增加（7.4%）。亚慢性预处理PSP（1 - 2 micromol/kg/天，腹腔注射）三天未影响甲苯磺丁脲的清除率和AUC，但Cinitial降低，同时T1/2和Vd增加。在急性和亚慢性研究中，体内4-羟基甲苯磺丁脲的形成均减少。综上所述，本研究表明PSP在体外和体内均可抑制甲苯磺丁脲4-羟化。尽管由于催化特性不同，大鼠和人肝脏中代谢甲苯磺丁脲的CYP同工酶不同，且大鼠研究结果可能无法直接外推至人类，但PSP与其他CYP2C底物合用时仍应谨慎监测。
