STEREOCHEMICAL STUDIES ON THE CYTOCHROME-P-450 CATALYZED OXIDATION OF (S)-NICOTINE TO THE (S)-NICOTINE DELTA-1'(5')-IMINIUM SPECIES
STEREOCHEMICAL STUDIES ON THE CYTOCHROME-P-450 CATALYZED OXIDATION OF (S)-NICOTINE TO THE (S)-NICOTINE DELTA-1'(5')-IMINIUM SPECIES
复制标题
DOI：
10.1021/jm00385a004
复制
发表时间：
1987-02-01
影响因子：
7.3
通讯作者：
CASTAGNOLI, N
中科院分区：
文献类型：
--
作者：
PETERSON, LA;TREVOR, A;CASTAGNOLI, N
哺乳动物将烟草生物碱(S)-尼古丁首先代谢为内酰胺(S)-可替宁，途径涉及起始的细胞色素P-450催化的前手性5‘-碳原子的双电子氧化。用人微粒体制剂和(S)-尼古丁-5‘’-D_1的E和Z非对映异构体研究了这种氧化的立体化学过程。通过毛细管柱GC-EIMS选择离子监测分析，捕获代谢生成的DELTA.1‘’(5‘’)-亚胺离子中间体，并将其作为相应的非对映异构体5‘’-氰基衍生物进行分析。这些研究的结果表明，这种生物转化是通过5‘-PRO-E质子的立体选择性提取进行的，即C-5’‘质子转化为大体积的吡啶基团。观察到的立体选择性与质子和氚的抽提无关。此外，(S)-可替宁的形成程度很小，并且不影响代谢衍生的α-氰基胺的立体化学组成。对雄性荷兰兔肝微粒体制剂的研究也得出了类似的结果。这些发现表明，(S)-尼古丁与细胞色素P-450活性中心形成的络合物的结构是高度有序的，并决定了反应途径的立体化学过程。
Mammals metabolize the tobacco alkaloid (S)-nicotine primarily to the lactam (S)-cotinine by a pathway involving an initial cytochrome P-450 catalyzed two-electron oxidation at the prochiral 5''-carbon atom. The stereochemical course of this oxidation was examined with human microsomal preparations and the E and Z diastereomers of (S)-nicotine-5''-d1. The metabolically generated .DELTA.1''(5'')-iminium ion intermediate was trapped and analyzed as the corresponding diastereomeric 5''-cyano derivatives by a capillary column GC-EIMS selected ion monitoring assay. The results of these studies established that this biotransformation proceeds with the stereoselective abstraction of the 5''-pro-E proton, that is, the C-5'' proton trans to the bulky pyridyl group. The observed stereoselectivity was independent of proton vs. deuteron abstraction. Additionally, the extent of (S)-cotinine formation was minor and did not influence the stereochemical composition of the metabolically derived .alpha.-cyano amines. Studies with male Dutch rabbit liver microsomal preparations gave similar results. These findings suggest that the structure of the complex formed between (S)-nicotine and the active site of cytochrome P-450 is highly ordered and dictates the stereochemical course of the reaction pathway.