Mechanism-based CYP2D6 inactivation by acridone alkaloids of Indonesian medicinal plant Lunasia amara

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• 作者：Naoto Takahashi ; Subehan ; Shigetoshi Kadota ; Yasuhiro Tezuka ; ^{tezuka@inm.u-toyama.ac.jp}
• 关键词：CYP ; cytochrome P450 ; NADP+ ; nicotinamide adenine dinucleotide phosphate ; G-6-P ; glucose-6-phosphate ; GSH ; N-acetyl-l-cysteine and glutathione reduced ; HLM ; human liver microsomes ; TLC ; thin layer chromatography ; kinact ; inactivation rate constant at infi
• 刊名：Fitoterapia
• 出版年：2012
• 期刊代码：35_0367326x
• 类别：ch
• 出版时间：June, 2012
• 卷：83
• 期：4
• 页码：774-779
• 文件大小：626 K

摘要

Fourteen acridone alkaloids isolated from Lunasia amara Blanco were tested for their mechanism-based inhibition on human liver microsomal dextromethorphan O-demethylation activity, a prototype marker for cytochrome P450 2D6 (CYP2D6). Among the 14 compounds, 5-hydroxygraveroline (1), 8-methoxyifflaiamine (2), lunamarine (3), and lunine (12) increased their inhibitory activity with increasing preincubation time. Then, we further examined the possibility of mechanism-based inhibition on 5-hydroxygraveroline (1) and lunamarine (3), which showed the potent inhibition. Further investigations on 1 and 3 showed that the characteristic time- and concentration-dependent inhibition, which required a catalytic step with NADPH, was not protected by nucleophiles, and was decreased by the presence of a competitive inhibitor. Thus, 1 and 3 were concluded as mechanism-based inactivators of CYP2D6.