欧前胡素是一种基于机制的CYP2B6失活剂。
Imperatorin is a mechanism-based inactivator of CYP2B6.
作者信息
Zheng Liwei, Cao Jiaojiao, Lu Dan, Ji Lin, Peng Ying, Zheng Jiang
机构信息
School of Pharmacy (L.Z., J.C., D.L., L.J., Y.P.), Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education (J.Z.), Shenyang Pharmaceutical University, Shenyang, Liaoning, P. R. China; and Center for Developmental Therapeutics, Seattle Children's Research Institute, Division of Gastroenterology and Hepatology, Department of Pediatrics, University of Washington School of Medicine, Seattle, Washington (J.Z.).
School of Pharmacy (L.Z., J.C., D.L., L.J., Y.P.), Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education (J.Z.), Shenyang Pharmaceutical University, Shenyang, Liaoning, P. R. China; and Center for Developmental Therapeutics, Seattle Children's Research Institute, Division of Gastroenterology and Hepatology, Department of Pediatrics, University of Washington School of Medicine, Seattle, Washington (J.Z.)
出版信息
Drug Metab Dispos. 2015 Jan;43(1):82-8. doi: 10.1124/dmd.114.060558. Epub 2014 Nov 5.
Imperatorin (IMP) is the major active ingredient in many common medicinal herbs. We examined the irreversible inhibitory effect of IMP on CYP2B6. IMP produced a time- and concentration-dependent inactivation of CYP2B6. About 70% of activity of CYP2B6 was suppressed after its incubation with 1.5 μM IMP for 9 minutes. KI and kinact were found to be 0.498 μM and 0.079 min(-1), respectively. The loss of CYP2B6 activity required the presence of NADPH. Glutathione and catalase/superoxide dismutase showed little protection against the IMP-induced enzyme inactivation. Ticlopidine, a substrate of CYP2B6, showed protection of the enzyme against the inactivation induced by IMP. The estimated partition ratio of the inactivation was approximately 4. Additionally, a γ-ketoenal intermediate was identified in microsomal incubations with IMP. CYP1A2, CYP2A6, CYP2B6, CYP2D6, CYP2E1, CYP3A4, and CYP3A5 were found to be involved in bioactivation of IMP. In conclusion, IMP is a mechanism-based inactivator of CYP2B6. The formation of γ-ketoenal intermediate may account for the enzyme inactivation.
欧前胡素（IMP）是许多常见草药中的主要活性成分。我们研究了IMP对CYP2B6的不可逆抑制作用。IMP对CYP2B6产生了时间和浓度依赖性的失活作用。将CYP2B6与1.5μM IMP孵育9分钟后，其约70%的活性被抑制。发现KI和kinact分别为0.498μM和0.079 min⁻¹。CYP2B6活性的丧失需要NADPH的存在。谷胱甘肽以及过氧化氢酶/超氧化物歧化酶对IMP诱导的酶失活几乎没有保护作用。噻氯匹定是CYP2B6的底物，它对该酶具有保护作用，使其免受IMP诱导的失活。失活的估计分配比约为4。此外，在与IMP的微粒体孵育中鉴定出了一种γ - 酮烯醛中间体。发现CYP1A2、CYP2A6、CYP2B6、CYP2D6、CYP2E1、CYP3A4和CYP3A5参与了IMP的生物活化。总之，IMP是一种基于机制的CYP2B6失活剂。γ - 酮烯醛中间体的形成可能是酶失活的原因。
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