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学科主题: 物理化学
题名: Hydroxylation of liquiritigenin in human liver microsomes is specifically catalyzed by cytochrome P4501A2
作者: Liu HX(刘慧鑫) ;  Yang L(杨凌)
会议名称: 16th North American Regional ISSX Meeting
会议日期: 2009-5-19
出版日期: 2009-05-19
会议地点: 美国
其他题名: 甘草素经P4501A2代谢机制研究
通讯作者: 杨凌
部门归属: 十八室
主办者: 国际药代会
摘要: Flavonoids are part of a family of naturally occurring polyphenolic compounds and represent one of the most prevalent classes of compounds in vegetables, nuts, fruits and beverages such as coffee, tea, and red wine as well as medical herbs. More than 8000 compounds with a flavonoid structure have been identified and categorized into flavonols, flavones, flavanones, isoflavones, catechins, anthocyanidins, and chalcones. Liquiritigenin is found most notably in Glycyrrhizae radix ,which is one of the oldest and most frequently used botanicals in the polyherbal preparations. G. radix exerts anticancer, antitussive, expectorant and antipyrotic actions and is often used to treat cough, pharyngitis, bronchitis, bronchial asthma. Liquiritigenin have been shown to have a inhibition of xanthine oxidase activity in vitro, dose related anti-allergic activities, and growth-inhibitory effect on cancer cell. It also has the anti-angiogenic effect, and antioxidant, anti-inflammatory activities. Six oxidative metabolites of liquiritigenin have been detected in rat liver microsomes (HLMs), and one CYP3A4-catalyzed metabolite has been identified in human liver microsomes (HLMs) recently. In the present study, a novel mono-hydroxylated metabolite was detected in reaction catalyzed by HLMs, and was identified as naringenin by comparing the tandem mass spectra and the chromatographic retention time with that of the standard compound. To identify and characterize the CYP isozymes involved in liquiritigenin hydroxylation, we examined liquiritigenin hydroxylation activities in HLM and rCYP incubation systems and compared the enzyme kinetic parameters between them. In addition, CYP reaction phenotyping of liquiritigenin was performed using a combination of three basic approaches as described by Bjornsson et al. : to determine whether heterologously expressed rCYPs were capable of metabolizing liquiritigenin; to examine the metabolic reaction in the absence and presence of CYP-selective chemical inhibitors; and to correlate the rate of the reaction with a CYP-selective marker activity across a panel of well characterized liver microsomal samples from individual donors. The kinetic profile followed Michaelis-Menten kinetics in HLM incubation system. The Eadie-Hofstee plot for liquiritigenin hydroxylation by HLMs was monophasic, suggesting that a single CYP isozyme is responsible for the hydroxylation. Furthermore, the Km value of liquiritigenin hydroxylation in HLMs was very close to that in rCYP2A6 (24.3 versus 25.6 µM). Among recombinant CYP isozymes examined in the present study, only the CYP1A2 isozyme exhibited liquiritigenin hydroxylation activity. In addition, the activities of liquiritigenin hydroxylation in 11 individual human liver microsomes were significantly correlated with the activities toward phenacetin, a proposed CYP1A2-selective probe substrate. Moreover, it is noteworthy that in HLMs, only furafylline (CYP1A2-selective inhibitor), but not other CYP-selective chemical inhibitors, inhibited the production of metabolite almost completely. These results suggest that CYP1A2 would specifically catalyze the liquiritigenin hydroxylation in human liver microsomes. Idenficiation of CYP1A2 as being responsible for liquiritigenin hydroxylation will greatly improve future investigations of CYP1A2 interindividual differences associated with liquiritigenin clinical trials and the magnitude of drug-drug interactions.
语种: 中文
内容类型: 会议论文
URI标识: http://cas-ir.dicp.ac.cn/handle/321008/113676
Appears in Collections:中国科学院大连化学物理研究所_会议论文

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Recommended Citation:
Liu HX,Yang L. Hydroxylation of liquiritigenin in human liver microsomes is specifically catalyzed by cytochrome P4501A2[C]. 见:16th North American Regional ISSX Meeting. 美国. 2009-5-19.
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