【作者】 董瑞华； 梁宇光； 朱亮亮； 房中则； 梁思成； 葛广波； 杨凌； 刘泽源；

【Author】 Rui-Hua Dong~1,Yu-Guang Liang~1,Liang-Liang Zhu~2,Zhong-Ze Fang~2,Si-Chang Liang~2,Guang-Bo Ge~2,Liang Yang~2,Ze-Yuan Liu~(1,*) (1 Department of Clinical Pharmacology,Affiliated Hospital,Academy of Military Medical Sciences.Beijing 100071,China; 2 Laboratory of Pharmaceutical Resource Discovery,Dalian Institute of Chemical Physics,Chinese Academy of Sciences,Dalian,116023,China)

【机构】 军事医学科学院附属医院药理室； 中国科学院大连化学物理研究所天然药物开发实验室；

【摘要】 <正>葡萄糖醛酸化是香芹酚的一个重要代谢途径。至今还没有人体内有关香芹酚葡萄糖醛酸化的代谢特征和关键酶的研究报道。本论文利用人肝微粒体(HLM),人肠微粒体(HIM),12个人源性重组葡萄糖苷酸转移酶单酶(UGT)和不同实验动物的肝微粒体对香芹酚的葡萄糖醛酸化的代谢特征进行了研究。香芹酚分别与更多还原

【Abstract】 Glucuronidation is an important pathway in the metabolism of carvacrol.However,the metabolites and primary UDP-glucuronosyltransferase（UGT） isozymes responsible for carvacrol glucuronidation remain to be determined in human.In the present study,the carvacrol glucuronidation were characterized by human liver microsomes（HLMs）, human intestinal microsomes（HIMs）,and 12 recombinant UGT（rUGT） isoforms,and experimental animal liver microsomes.One metabolite were indentified as monoglucuronides by liquid chromatography/mass spectrometry with HLMs,HIMs, rUGTlA3,rUGTlA6,rUGT1A7,rUGTlA9 and rUGT2B7.A kinetic study showed that carvacrol glucuronidation by HLMs and UGT1A9,HLMs and UGT1A7 followed Substrance-Inhibiton and Michaelis-Menten kinetics,respectively.The K_m values of HLMs,HIMs,rUGTlA9,and rUGTlA7 for carvacrol glucuronidation were as follows: 80.70±16.73,260.22±44.18,78.44±15.90,282.61±37.33 uM for M-l,respectively. The carvacrol glucuronidation in different experiment animal showed the species difference was not large.A chemical inhibition study showed that the IC₅₀ for propofol inhibiton of carvacrol glucuronidation was similar in HLMs（187.4±60.56uM ） compared with rUGTlA9（194.4±48.73uM ） and in HIMs（162.48±55.90 uM） compared with rUGT1A7（154.72±59.86 uM ）.In contrast,rUGTlA3,rUGTlA6 and rUGT2B7 do not showed that obviously propofol inhibiton of carvacrol glucuronidation. In combination,we identified rGUT1A9 as the major isozyme responsible for glucuronidation in HLMs,and rGUT1 A7 play the major isoforms for glucuronidation in HLMs.更多还原