Sauer Christoph, Peters Frank T, Schwaninger Andrea E, Meyer Markus R, Maurer Hans H
Department of Experimental and Clinical Toxicology, Institute of Experimental and Clinical Pharmacology and Toxicology, Saarland University, D-66421 Homburg, Saar, Germany.
Chem Res Toxicol. 2008 Oct;21(10):1949-55. doi: 10.1021/tx8001302. Epub 2008 Sep 9.
The involvement of human hepatic cytochrome P450 isoenzymes (P450s) in the metabolism of the designer drugs N-(1-phenylcyclohexyl)-3-ethoxypropanamine (PCEPA) and N-(1-phenylcyclohexyl)-3-methoxypropanamine (PCMPA) to the common metabolite N-(1-phenylcyclohexyl)-3-hydroxypropanamine (PCHPA) was studied using insect cell microsomes with cDNA-expressed human P450s and human liver microsomes (HLMs). Incubation samples were analyzed by gas chromatography-mass spectrometry or liquid chromatography-mass spectrometry. Among the tested isoenzymes, P450 2B6, P450 2C19, P450 2D6, and P450 3A4 catalyzed PCEPA O-deethylation, and P450 2B6, P450 2C19, and P450 2D6 catalyzed PCMPA O-demethylation. According to the relative activity factor approach, these enzymes accounted for 22, 3, 30, and 45% of the net clearance for PCEPA and 51, 8, and 40% of the net clearance for PCMPA, respectively. At 1 microM PCEPA, the chemical inhibitors 4-(4-chlorobenzyl)pyridine for P450 2B6 and quinidine for P450 2D6 reduced metabolite formation in pooled HLMs by 37 and 73%, respectively, and at 10 microM PCEPA, they reduced metabolite formation by 57 and 26%, respectively. At 1 microM PCMPA, 4-(4-chlorobenzyl)pyridine and quinidine reduced metabolite formation in pooled HLMs by 25 and 39%, respectively, and at 10 microM PCMPA, they reduced metabolite formation by 62 and 27%, respectively. The experiments with the MAB inhibitory to P450 3A4 and the chemical inhibitor ketoconazole for P450 3A4 showed no inhibitory effect concerning PCEPA O-dealkylation. Experiments with HLMs from P450 2D6 poor metabolizers showed a reduction of metabolite formation as compared to pooled HLM of 73 and 25% (1 microM and 10 microM PCEPA) and 40 and 38% (1 microM and 10 microM PCMPA), respectively. In conclusion, the main metabolic step was catalyzed by different P450s.
利用表达人细胞色素P450（P450s）cDNA的昆虫细胞微粒体和人肝微粒体（HLMs），研究了人肝细胞色素P450同工酶（P450s）在新型毒品N-(1-苯基环己基)-3-乙氧基丙胺（PCEPA）和N-(1-苯基环己基)-3-甲氧基丙胺（PCMPA）代谢生成共同代谢产物N-(1-苯基环己基)-3-羟基丙胺（PCHPA）过程中的作用。通过气相色谱-质谱联用或液相色谱-质谱联用对孵育样品进行分析。在所测试的同工酶中，P450 2B6、P450 2C19、P450 2D6和P450 3A4催化PCEPA的O-脱乙基反应，P450 2B6、P450 2C19和P450 2D6催化PCMPA的O-脱甲基反应。根据相对活性因子法，这些酶分别占PCEPA净清除率的22%、3%、30%和45%，以及PCMPA净清除率的51%、8%和40%。在1μM PCEPA时，P450 2B6的化学抑制剂4-(4-氯苄基)吡啶和P450 2D6的化学抑制剂奎尼丁分别使混合HLMs中代谢产物的生成减少37%和73%，在10μM PCEPA时，分别减少57%和26%。在1μM PCMPA时，4-(4-氯苄基)吡啶和奎尼丁分别使混合HLMs中代谢产物的生成减少25%和39%，在10μM PCMPA时，分别减少62%和27%。对P450 3A4有抑制作用的单克隆抗体（MAB）和P450 3A4的化学抑制剂酮康唑的实验表明，它们对PCEPA的O-脱烷基反应没有抑制作用。用P450 2D6慢代谢者的HLMs进行的实验表明，与混合HLMs相比，代谢产物的生成分别减少了73%和25%（1μM和10μM PCEPA）以及40%和38%（1μM和10μM PCMPA）。总之，主要的代谢步骤由不同的P450催化。
Zotero 插件