Characterization of major phytocannabinoids, cannabidiol and cannabinol, as isoform-selective and potent inhibitors of human CYP1 enzymes
Characterization of major phytocannabinoids, cannabidiol and cannabinol, as isoform-selective and potent inhibitors of human CYP1 enzymes
复制标题
DOI：
10.1016/j.bcp.2010.01.028
复制
发表时间：
2010-06-01
影响因子：
5.8
通讯作者：
Watanabe, Kazuhito
中科院分区：
文献类型：
--
作者：
Yamaori, Satoshi;Kushihara, Mika;Watanabe, Kazuhito
Delta(9)-四氢大麻酚(Delta(9)-THC)、大麻二酚(CBD)的抑制作用。和大麻酚(CBN)对人细胞色素P450(CYP)1酶催化活性的影响。这些大麻素以竞争性的方式抑制重组细胞色素P1A1、细胞色素P1A2和细胞色素P1B1的7-乙氧基间苯二酚O-脱乙基酶活性。COD对细胞色素P4501A1的抑制作用最强，表观K-I值(0.155µM)至少是其他亚型的十七分之一。另一方面，CBN对细胞色素P1A2和细胞色素P1B1活性的抑制作用(K-I分别为0.0790和0.148 mU/M)明显高于细胞色素P1A1(K-I=0.541 mU/M)。Delta(9)-THC对该酶的抑制作用弱于CBD和CBN，对该酶的抑制表现出较低的选择性(K-I=2.47-7.54 mU M)。CBD预孵育后，所有重组细胞色素P4 1酶和人肝微粒体的催化活性均呈时间和浓度依赖性下降。同样，Delta(9)-THC或CBN预孵育对重组细胞色素P1A1的抑制呈时间和浓度依赖性。CBD对细胞色素P4501A1的失活表明，在所测试的酶来源中，k(Inact)/K-I值最高(540 L/mmoL/min)。CBD对重组细胞色素P1A1和人肝微粒体的灭活需要NADPH，不受透析和谷胱甘肽、N-乙酰半胱氨酸和超氧化物歧化酶等捕捉剂的影响。这些结果表明，CBD和CBN对细胞色素P450 1有选择性的直接抑制作用，CBD是一种有效的基于机制的抑制人细胞色素P450 1酶，尤其是细胞色素P1A1。(C)2010 Elsevier Inc.保留所有权利。
Inhibitory effects of Delta(9)-tetrahydrocannabinol (Delta(9)-THC), cannabidiol (CBD). and cannabinol (CBN), the three major constituents in marijuana, on catalytic activities of human cytochrome P450 (CYP) 1 enzymes were investigated. These cannabinoids inhibited 7-ethoxyresorufin O-deethylase activity of recombinant CYP1A1, CYP1A2, and CYP1B1 in a competitive manner. COD most potently inhibited the CYP1A1 activity; the apparent K-i value (0.155 mu M) was at least one-seventeenth of the values for other CYP1 isoforms. On the other hand, CBN more effectively decreased the activity of CYP1A2 and CYP1B1 (K-i = 0.0790 and 0.148 mu M, respectively) compared with CYP1A1 (K-i = 0.541 mu M). Delta(9)-THC less potently inhibited the CYP1 activity than CBD and CBN, and showed low selectivity against the CYP1 inhibition (K-i = 2.47-7.54 mu M). The preincubation of CBD resulted in a time- and concentration-dependent decrease in catalytic activity of all the recombinant CYP1 enzymes and human liver microsomes. Similarly, the preincubation of Delta(9)-THC or CBN caused a time- and concentration-dependent inhibition of recombinant CYP1A1. The inactivation of CYP1A1 by CBD indicated the highest k(inact)/K-I value (540 l/mmol/min) among the CYP1 enzyme sources tested. The inactivation of recombinant CYP1A1 and human liver microsomes by CBD required NADPH, was not influenced by dialysis and by glutathione, N-acetylcysteine, and superoxide dismutase as trapping agents. These results indicated that CBD and CBN showed CYP1 isoform-selective direct inhibition and that CBD was characterized as a potent mechanism-based inhibitor of human CYP1 enzymes, especially CYP1A1. (C) 2010 Elsevier Inc. All rights reserved.