细胞色素 P450 酶和尿苷二磷酸葡萄糖醛酸基转移酶在人及动物肝微粒体中对荷叶碱代谢的特征。
Characterization of nuciferine metabolism by P450 enzymes and uridine diphosphate glucuronosyltransferases in liver microsomes from humans and animals.
机构信息
Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China.
出版信息
Acta Pharmacol Sin. 2010 Dec;31(12):1635-42. doi: 10.1038/aps.2010.172.
AIM
to characterize the metabolism of nuciferine by P450 enzymes and uridine diphosphate glucuronosyltransferase (UGT) in liver microsomes from humans and several other animals including rats, mice, dogs, rabbits and monkeys.
METHODS
nuciferine was incubated with both human and animal liver microsomal fractions containing P450 or UGT reaction components. Ultra performance liquid chromatography coupled with mass spectrometry was used to separate and identify nuciferine metabolites. Chemical inhibition was used to identify the involved isozymes. Species difference of nuciferine metabolism in human and various animals were investigated in the liver microsomal incubation system.
RESULTS
among the nuciferine metabolites detected and identified, seven were catalyzed by P450 and one by UGT. Ketoconazole inhibited the formation of M292, M294 and M312. Furafylline, 8-methoxypsoralen and quercetin inhibited the formation of M282. Hecogenin showed a significant inhibitory effect on nuciferine glucuronidation. While the P450-catalyzed metabolites showed no species differences, the glucuronidation product was only detected in microsomes from humans and rabbits.
CONCLUSION
the isozymes UGT 1A4, CYP 3A4, 1A2, 2A6 and 2C8 participated in the hepatic metabolism of nuciferine. Based on the observed species-specific hepatic metabolism of nuciferine, rats, mice, dogs and even monkeys are not suitable models for the pharmacokinetics of nuciferine in humans.
目的
在人肝微粒体以及大鼠、小鼠、犬、兔和猴等其他几种动物的肝微粒体中，研究 P450 酶和尿苷二磷酸葡萄糖醛酸基转移酶（UGT）对荷叶碱代谢的作用。
方法
用含 P450 或 UGT 反应成分的人及动物肝微粒体部分孵育荷叶碱。采用超高效液相色谱-质谱联用技术分离并鉴定荷叶碱代谢产物。用化学抑制法鉴定参与的同工酶。用人及各种动物肝微粒体孵育体系研究荷叶碱在体内的代谢种属差异。
结果
在所检测和鉴定的荷叶碱代谢产物中，有 7 种产物由 P450 催化，1 种产物由 UGT 催化。酮康唑抑制 M292、M294 和 M312 的形成。呋喃氟醇、8-甲氧基补骨脂素和槲皮素抑制 M282 的形成。海柯苷对荷叶碱的葡萄糖醛酸化有显著的抑制作用。虽然 P450 催化的代谢产物没有种属差异，但葡萄糖醛酸化产物仅在人及兔肝微粒体中检测到。
结论
UGT1A4、CYP3A4、1A2、2A6 和 2C8 同工酶参与了荷叶碱的肝内代谢。根据观察到的荷叶碱在肝脏中的种属特异性代谢，大鼠、小鼠、犬，甚至猴子均不适合作为研究荷叶碱在人体内药代动力学的模型。
Zotero 插件