Subject Area物理化学
Inhibitory Effects of Dibenzocyclooctadiene lignans from Fructus schisandrae on CYP2C8-mediated Paclitaxel Metabolism in Human Liver Microsomes
Zhang YY(张延延); Yang L(杨凌)
Conference Name3rd Asian Pacific Regional Meeting of the International-Society-for-the-Study-of-Xenobiotics
Conference Date2009-5-10
Conference PlaceTHAILAND
Alternative Title五味子木脂素成分对CYP2C8介导的紫杉醇代谢抑制作用
AbstractInhibitory Effects of Dibenzocyclooctadiene Lingans from Fructus Schisandrae on CYP2C8-Mediated Paclitaxel Metabolism in Human Liver Microsomes Yan-Yan Zhang, Ling Yang Laboratory of Pharmaceutical Resource Discovery, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan Road, Dalian, 116023 China Dibenzocyclooctadiene lingans are the principle active ingredients of Fructus Schisandrae, which is extensively used as an antitussive, sedative and tonic agent in China, Korea, Japan and Russia. According to Chinese Pharmacopoeia 2005 edition, these lingans are recognized as the major constituents in this Chinese herb medicine. Recently, schisandra extract and some purified lingans have been found to enhance the efficacy of paclitaxel against multidrug resistance tumor cell lines1. In the present study, an in vitro study was undertaken to evaluate the influence of 7 major Schisandra lingans on CYP2C8, which is the primary metabolic enzyme for paclitaxel. Among all these components, gomisin G (IC50=4.3±0.7 µM) exhibited the most potent inhibitory effect on CYP2C8-dependent paclitaxel 6α-hydroxylation in noncompetitive manner, with apparent Ki value of 4.1 µM. Gomisin A (IC50= 8.7±0.8 µM, Ki=8.6 µM) and pregomisin (IC50= 9.3±0.8 µM, Ki=8.0 µM) were also found to potently inhibit CYP2C8 in noncompetitive and competitive manner, respectively. However, schizandrol A (IC50>100 µM), schizandrin A (IC50= 31.8±1.7 µM), B (IC50= 12.6±1.9 µM) and C (IC50>100 µM) were considered less likely to cause drug-drug interactions via inhibition of CYP2C8 activity. Since paclitaxel holds a complex pharmacological and toxicological profile with a narrow therapeutic window2, special attention should be taken on the alteration of paclitaxel pharmacokinetic behavior, when coadministered with the corresponding dibenzocyclooctadiene lingans or the crude extract of Fructus Schisandrae. Reference 1. Huang M, Jin J, Sun H, Liu GT. Reversal of P-glycoprotein-mediated multidrug resistance of cancer cells by five schizandrins isolated from the Chinese herb Fructus Schizandrae. Cancer Chemother Pharmacol 2008 62(6):1015-1026. 2. Mielke S, Sparreboom A, Steinberg SM, Gelderblom H, Unger C, Behringer D, Mross K. Association of Paclitaxel pharmacokinetics with the development of peripheral neuropathy in patients with advanced cancer. Clin Cancer Res 2005 11(13): 4843-4850.
WOS IDWOS:000269483300178
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Document Type会议论文
Corresponding AuthorYang L(杨凌)
Recommended Citation
GB/T 7714
Zhang YY,Yang L. Inhibitory Effects of Dibenzocyclooctadiene lignans from Fructus schisandrae on CYP2C8-mediated Paclitaxel Metabolism in Human Liver Microsomes[C],2009:87/2.
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