药物代谢酶抑制剂对反式二苯乙烯苷所致肝损伤易感性的影响  

Influence of drug metabolizing enzyme inhibitors on liver injury susceptibility to trans-2,3,5,4'-tetrahydroxystilbene-2-O-β-D-glucoside

作　　者：李娜[1,2] 宋捷[1] 李晓菲[2] 王亚[2] 孟雅坤 涂灿[2] 李春雨[3] 马致洁[2] 庞晶瑶 李瑞煜[2] 肖小河[4] 康廷国[1] 王伽伯[2] 

机构地区：[1]辽宁中医药大学药学院,辽宁大连116600 [2]解放军302医院全军中医药研究所,北京100039 [3]中国医学科学院北京协和医学院药用植物研究所,北京100193 [4]解放军302医院中西医结合肝病诊疗与研究中心,北京100039

出　　处：《药学学报》2017年第7期1063-1068,共6页Acta Pharmaceutica Sinica

基　　金：国家自然科学基金青年基金资助项目(81503350);国家"重大新药创制"科技重大专项课题(2015ZX09501-004-001-008);国家公益性行业科研专项课题(201507004-04);全军医学科技"十二五"科研项目(BWS11J049)

摘　　要：采用药物代谢酶抑制剂,考察代谢因素对何首乌中主要成分反式二苯乙烯苷潜在肝损伤作用的影响,并筛查反式二苯乙烯苷的主要代谢酶亚型。结果表明,在内毒素(LPS)复制的大鼠肝损伤易感性模型内,反式二苯乙烯苷(trans-SG,31 mg·kg^(-1))未引起肝损伤作用,进一步联合Ⅰ相代谢酶抑制剂苄基咪唑(10 mg·kg^(-1))未改变trans-SG的肝损伤程度(与LPS+trans-SG组相比P>0.05);而联合Ⅱ相代谢酶抑制剂酮康唑(35 mg·kg^(-1))显著增加了trans-SG的肝损伤程度(与LPS+trans-SG组相比P<0.05)。在人肝微粒体Ⅰ相代谢孵育体系中,未检测到trans-SG代谢产物;在人重组UGT同工酶Ⅱ相代谢孵育体系中,检测到trans-SG的葡糖醛酸代谢物,6个尿苷二磷酸葡糖醛酸转移酶(UGT)亚型的代谢能力依次为:UGT1A1>UGT1A9>UGT1A7>UGT1A10>UGT2B7>UGT1A8。结果提示:trans-SG主要经由UGT介导的Ⅱ相代谢,抑制药物Ⅱ相代谢酶可增加trans-SG潜在的肝损伤风险。这为何首乌易感因素评价和药物配伍禁忌研究提供了参考依据。By using the drug metabolizing enzyme inhibitors, the effects of metabolic factors on potential liver injury induced by the main component, trans-2,3,5,4＇-tetrahydroxystilbene-2-O-β-D-glucoside（trans-SG）, in Polygonum multiflorum was investigated. The main metabolic enzyme isoforms involved in trans-SG metabolism were also screened. The results showed that trans-SG at the dosage 31 mg·kg^（-1） did not cause liver injury; and the combination of trans-SG with the phase Ⅰ metabolic enzyme inhibitor, 1-benzylimidazole（10 mg·kg^（-1））, did not change the degree of liver injury（compared with LPS ＋ trans-SG group, P 0.05）. However, the combination of trans-SG with phase Ⅱ metabolic enzyme inhibitor, ketoconazole（35 mg·kg^（-1））, significantly increased the degree of liver injury（compared with LPS ＋ trans-SG group, P 0.05）. The phase Ⅰ metabolites of trans-SG were not detected in human liver microsomes phase Ⅰ metabolism system, while the phase Ⅱ trans-SG metabolites were detected in recombinant human UGT isozymes phase Ⅱ metabolism system. Six isoforms of uridine diphosphate glucuronate transferase（UGT） exhibited abilities to metabolize trans-SG and the order of metabolic ability was： UGT1A1 UGT1A9 UGT1A7 UGT1A10 UGT2B7 UGT1A8. The results showed that trans-SG was mainly metabolized by UGT in phase Ⅱ metabolism. The inhibition of drug metabolizing enzymes of phase Ⅱ can increase the liver injury susceptibility of trans-SG, which provides a reference to the evaluation of susceptible factors and drug incompatibility research of Polygonum multiflorum.

关 键 词：何首乌 反式二苯乙烯苷 肝损伤 代谢因素 Ⅰ相代谢 Ⅱ相代谢 

分 类 号：R963[医药卫生—微生物与生化药学]