Tateishi T, Krivoruk Y, Ueng Y F, Wood A J, Guengerich F P, Wood M
Department of Anesthesiology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-2125, USA.
Anesth Analg. 1996 Jan;82(1):167-72. doi: 10.1097/00000539-199601000-00031.
Alfentanil, sufentanil, and fentanyl are synthetic opioids that are metabolized by oxidative N-dealkylation in the liver. We have previously shown that cytochrome P-450 3A4 (CYP3A4) contributes significantly to human liver microsomal alfentanil oxidation. Since identification of specific drug-metabolizing enzymes allows prediction of the variables affecting drug metabolism, the purpose of the present study was to identify the P-450 enzymes responsible for sufentanil and fentanyl metabolism in human liver microsomes. Microsomal preparations fortified with a reduced nicotinamide-adenine dinucleotide phosphate-generating system were incubated with 0.25 microM 3H-fentanyl or 3H-sufentanil. Rates of N-dealkylated metabolite formation significantly correlated with nifedipine oxidation activity (a marker of CYP3A4 activity) for fentanyl and sufentanil (r = 0.93 and 0.87, n = 18, respectively), but not with the oxidation activity for ethoxyresorufin (CYP1A2), S-mephenytoin (CYP2C19), bufuralol (CYP2D6), or chlorzoxazone (CYP2E1). Gestodene and troleandomycin (chemical inhibitors of CYP3A4) and antibody to CYP3A4 inhibited N-dealkylation of fentanyl and sufentanil. Chemical inhibitors of CYP2C, 2E1, and 2D6 did not inhibit N-dealkylation of fentanyl and sufentanil. Recombinant CYP3A4 expressed in Escherichia coli showed N-dealkylation activity of fentanyl and sufentanil, while expressed CYP1A2, 2C10, and 2E1 enzymes did not. We conclude that CYP3A4 is responsible for fentanyl and sufentanil N-dealkylation in vitro.
阿芬太尼、舒芬太尼和芬太尼是合成阿片类药物，在肝脏中通过氧化N-脱烷基作用进行代谢。我们之前已经表明，细胞色素P-450 3A4（CYP3A4）对人肝微粒体阿芬太尼氧化起重要作用。由于鉴定特定的药物代谢酶可预测影响药物代谢的变量，本研究的目的是鉴定人肝微粒体中负责舒芬太尼和芬太尼代谢的P-450酶。用还原型烟酰胺腺嘌呤二核苷酸磷酸生成系统强化的微粒体制剂与0.25微摩尔的3H-芬太尼或3H-舒芬太尼一起孵育。芬太尼和舒芬太尼的N-脱烷基代谢物形成速率与硝苯地平氧化活性（CYP3A4活性的标志物）显著相关（r分别为0.93和0.87，n = 18），但与乙氧萘胺（CYP1A2）、S-美芬妥因（CYP2C19）、布非洛尔（CYP2D6）或氯唑沙宗（CYP2E）的氧化活性无关。孕二烯酮和三乙酰竹桃霉素（CYP3A4的化学抑制剂）以及抗CYP3A4抗体抑制芬太尼和舒芬太尼的N-脱烷基作用。CYP2C、2E1和2D6的化学抑制剂不抑制芬太尼和舒芬太尼的N-脱烷基作用。在大肠杆菌中表达的重组CYP3A4显示出芬太尼和舒芬太尼的N-脱烷基活性，而表达的CYP1A2、2C10和2E1酶则没有。我们得出结论，CYP3A4在体外负责芬太尼和舒芬太尼的N-脱烷基作用。
