Inhibition of CYP2B4 by the mechanism-based inhibitor 2-ethynylnaphthalene: Inhibitory potential of 2EN is dependent on the size of the substrate
Inhibition of CYP2B4 by the mechanism-based inhibitor 2-ethynylnaphthalene: Inhibitory potential of 2EN is dependent on the size of the substrate
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DOI：
10.1016/j.abb.2007.03.023
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发表时间：
2007-06-01
影响因子：
3.9
通讯作者：
Backes, Wayne L.
中科院分区：
文献类型：
--
作者：
Cheng, Dongmei;Reed, James R.;Backes, Wayne L.
2-乙炔基萘(2EN)是一种基于机理的CYP2B4抑制剂，包括两种成分：(1)需要与2EN代谢物共价结合的酶失活；(2)2EN自身的可逆抑制。用几种不同的CYP2B4底物检测了这两种抑制成分。2EN与CYP2134预先孵育导致所研究的每一种依赖于CYP2B4的活性的时间依赖性失活；然而，2EN可逆地抑制CYP2B4的能力取决于所用的底物，这与经典的抑制模式不一致。2EN的可逆抑制程度与底物对活性部位的亲和力无关，而与底物的分子大小有关。结果与2EN一致，较小的底物同时适合于CYP2B4活性部位，导致抑制作用很小。较大的底物表现出更大程度的抑制，因为它们不能与活性部位的抑制剂共结合。(C)2007 Elsevier Inc.保留所有权利。
2-Ethynylnaphthalene (2EN) is a mechanism-based inhibitor of CYP2B4 with two components to the inhibition, (1) enzyme inactivation, which requires covalent binding of the 2EN metabolite, and (2) reversible inhibition by 2EN itself. Both inhibitory components were examined using several different CYP2B4 substrates. Preincubation of CYP2134 with 2EN led to a time-dependent inactivation of each of the CYP2B4-dependent activities examined; however, the ability of 2EN to reversibly inhibit CYP2B4 depended on the substrate employed, which is inconsistent with classical inhibition patterns. The degree 2EN's reversible inhibition was shown not to correlate with the substrate affinity for the active site, but with parameters related to the molecular size of the substrate. The results are consistent with 2EN and the smaller substrates simultaneously fitting in the CYP2B4 active site, leading to very little inhibition. Larger substrates exhibited greater degrees of inhibition because of their inability to co-bind with inhibitor in the active site. (C) 2007 Elsevier Inc. All rights reserved.