Comparative aromatic hydroxylation and N-demethylation of MPTP neurotoxin and its analogs, N-methylated β-carboline and isoquinoline alkaloids, by human cytochrome P450 2D6
Comparative aromatic hydroxylation and N-demethylation of MPTP neurotoxin and its analogs, N-methylated β-carboline and isoquinoline alkaloids, by human cytochrome P450 2D6
复制标题
DOI：
10.1016/j.taap.2006.06.003
复制
发表时间：
2006-11-01
影响因子：
3.8
通讯作者：
Gonzalez, Frank J.
中科院分区：
文献类型：
--
作者：
Herraiz, Tomas;Guillen, Hugo;Gonzalez, Frank J.
1-甲基-4-苯基-1，2，3，6-四氢吡啶（MPTP）神经毒素是帕金森病（PD）的化学诱导剂，而N-甲基化β-咔啉和异喹啉是参与PD的MPTP的天然存在的类似物。本研究研究了人CYP 2D 6（CYP 2D 6 *1和CYP 2D 6 *10等位基因变体）以及类似于细胞色素P450的混合物HIM对MPTP的氧化，并将产生的产物与人单胺氧化酶（MAO-B）提供的产物进行了比较。MPTP被CYP 2D 6有效氧化为两种主要产物：MPTP-OH（p-羟基化）和PTP（N-去甲基化），转换数为10.09 min（-1），K-m为79.36 +/- 3 mu M（形成MPTP-OH）和18.95 min（-1），K-m为69.6 +/- 2.2 mu M（PTP）。还检测到少量脱氢毒素MPDP+和MPP+。CYP 2D 6与MAO-B竞争MPTP的氧化。MAO-B将MPTP氧化为MPDP+和MPP+毒素（生物活化）比CYP 2D 6解毒为PTP和MPTP-OH高3倍。筛选了几种N-甲基化β-咔啉和异喹啉的N-去甲基化（解毒），其不被CYP 2D 6或显著催化。P450混合物相比之下，各种β-咔啉通过CYP 2D 6有效地羟基化为羟基-β-咔啉。因此，N（2）-甲基-1，2，3，4-四氢-β-咔啉（一种接近的MPTP类似物）被高度羟基化为6-羟基-N（2）-甲基-1，2，3，4-四氢-β-咔啉和相应的7-羟基衍生物。因此，CYP 2D 6可以通过活性羟基化途径参与这些神经活性化合物的生物活化和/或解毒。与CYP 2D 6 *10变体相比，CYP 2D 6 *1酶变体表现出更高的MPTP和N（2）-甲基-1，2，3，4-四氢-β-咔啉代谢，突出了CYP 2D 6多态性在这些毒素氧化中的重要性。总之，这些结果表明，CYP 2D 6可以在MPTP和β-咔啉的代谢结果中发挥重要作用。爱思唯尔公司出版
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxin is a chemical inducer of Parkinson's disease (PD) whereas N-methylated beta-carbolines and isoquinolines are naturally occurring analogues of MPTP involved in PD. This research has studied the oxidation of MPTP by human CYP2D6 (CYP2D6*1 and CYP2D6*10 allelic variants) as well as by a mixture of cytochrome P450s-resembling HIM, and the products generated compared with those afforded by human monoamine oxidase (MAO-B). MPTP was efficiently oxidized by CYP2D6 to two main products: MPTP-OH (p-hydroxylation) and PTP (N-demethylation), with turnover numbers of 10.09 min(-1) and K-m of 79.36 +/- 3 mu M (formation of MPTP-OH) and 18.95 min(-1) and K-m 69.6 +/- 2.2 mu M (PTP). Small amounts of dehydrogenated toxins MPDP+ and MPP+ were also detected. CYP2D6 competed with MAO-B for the oxidation of MPTP. MPTP oxidation by MAO-B to MPDP+ and MPP+ toxins (bioactivation) was up to 3-fold higher than CYP2D6 detoxification to PTP and MPTP-OH. Several N-methylated beta-carbolines and isoquinolines were screened for N-demethylation (detoxification) that was not significantly catalyzed by CYP2D6 or. the P450s mixture. In contrast, various beta-carbolines were efficiently hydroxylated to hydroxy-beta-carbolines by CYP2D6. Thus, N(2)-methyl-1,2,3,4-tetrahydro-beta-carboline (a close MPTP analog) was highly hydroxylated to 6-hydroxy-N(2)-methyl-1,2,3,4-tetrahydro-beta-carboline and a corresponding 7-hydroxy-derivative. Thus, CYP2D6 could participate in the bioactivation and/or detoxification of these neuroactive compounds by an active hydroxylation pathway. The CYP2D6*1 enzymatic variant exhibited much higher metabolism of both MPTP and N(2)-methyl-1,2,3,4-tetrahydro-beta-carboline than the CYP2D6*10 variant, highlighting the importance of CYP2D6 polymorphism in the oxidation of these toxins. Altogether, these results suggest that CYP2D6 can play an important role in the metabolic outcome of both MPTP and beta-carbolines. Published by Elsevier Inc.