目的研究苯环喹溴铵对大鼠肝脏CYP450酶是否有诱导作用。方法将SD大鼠，分为空白溶剂组、阳性对照组和苯环喹溴铵低中高剂量给药组(分别鼻腔给予苯环喹溴铵生理盐水溶液1，3或9mg·kg-1)，分别于连续给药后处死，取肝称重并制备微粒体。计算大鼠肝脏脏器系数;测定大鼠肝脏微粒体CYP450蛋白含量;通过HPLC-MS/MS测定大鼠肝微粒体温孵体系中6β-羟基睾酮和对乙酰氨基酚的浓度;应用底物法测定大鼠肝微粒体CYP1A1/2和CYP3A1/2酶的活性。结果阳性对照组与空白溶剂组相比，在大鼠肝脏脏器系数、CYP450蛋白含量及CYP1A1/2和CYP3A1/2酶活性上均有增加，且具有显著性差异(P<0.05)。苯环喹溴铵低中高剂量给药组与空白溶剂组在肝脏脏器系数、CYP450蛋白含量和CYP1A1/2酶活性上均无显著性差异(P>0.05);苯环喹溴铵低中高剂量给药组大鼠肝脏CYP3A1/2酶的活性未高于空白溶剂组。结论阳性对照组对大鼠肝脏CYP450酶有诱导作用，所建立的实验体系可用于诱导作用的评价;苯环喹溴铵低中高3个剂量组对大鼠肝脏CYP450酶均无诱导作用。
Abstract
OBJECTIVE To study the induction effect of bencycloquidium bromide (BCQB) on rat liver cytochrome P450 enzymes. METHODS Rats were divided into solvent control group,positive control (phenobarbital) group and BCQB group. The rats in BCQB groups were intranasally administered with 1,3,and 9 mg·kg-1 BCQB,respectively. After multiple-dose administration,the rats were sacrificed,and the livers were weighed and prepared to microsomes.Then the liver coefficients were calculated,and the total content of CYP450 enzymes in liver microsomes was determined by spectrophotometer. HPLC-MS/MS method was adopted and validated to simultaneously determine the productive velocity of 6β-hydroxyl testosterone and paracetamol after incubation of rat liver microsomes. The activities of CYP1A1/2 and CYP3A1/2 were measured according to the productive velocity. RESULTS The liver coefficients,total content of CYP450 enzymes,and activity of CYP1A1/2 were significantly different (P<0.05) between solvent control group and positive control group,while comparable (P>0.05) between solvent control group and BCQB groups. The activity of CYP3A1/2 in BCQB groups was not higher than solvent control group. CONCLUSION Phenobarbital has induction effect on rat liver CYP450 enzymes. The test system can be used to evaluate the induction effect of BCQB on rat liver CYP450 enzymes. BCQB has no induction effect on liver CYP450 enzymes in rats.
关键词
苯环喹溴铵 /
大鼠肝微粒体 /
诱导 /
底物法 /
细胞色素P450
{{custom_keyword}} /
Key words
bencycloquidium bromide /
rat liver microsome /
induction /
probe substrates method /
CYP450
{{custom_keyword}} /
中图分类号：
R965
{{custom_clc.code}}
({{custom_clc.text}})
{{custom_sec.title}}
{{custom_sec.title}}
{{custom_sec.content}}
参考文献
[1] JIANG J X,CAO R,DENG W D,et al.Characterization of bencycloquidium bromide,a novel muscarinic M3 receptor antagonist in guinea pig airways .Eur J Pharmacol,2011,655: 74-82.[2] LI J,HE H X,ZHOU Y D,et al.Selectivity of bencycloquidium bromide to subtypes of muscarinic acetylcholine receptors .Chin J New Drugs Clin Rem (中国新药与临床杂志),2010,29(1): 45-49.[3] ZHAO S Q.Quinuclidine compounds having quaternary ammonium group,its preparation method and use as blocking agents of acetycholine: World,WO 2006/029549 A1 .3006-3-23.[4] SHI C,WU C Q,CAO A M,et al.Induction of rat liver cytochrome P450 by 2-heteroaryl-dihydropyrimidines (Bay41-4109) .Chin J New Drugs (中国新药杂志),2007,6(20): 1666-1669.[5] XU L J,JU W Z,CHEN W K,et al.Effects of the erigeron injection on liver microsomal cytochrome P450 system in mice .Chin J Clin Pharmacol Ther (中国临床药理学与治疗学),2008,13(10): 1122-1126.[6] ZENG S.Drug Metabolism (药物代谢学) .Hangzhou: Zhejiang University Press,2008: 340-343.[7] ZHU L Q,LOU J S.Resent studies on cytochrome P450 and drug metabolism .Chin J Clin Pharmacol Ther (中国临床药理学与治疗学),2004,9(10): 1081-1086.[8] ZENG S.Drug Metabolism (药物代谢学) .Hangzhou: Zhejiang University Press,2008: 359.[9] YUAN R,MADANI S,WEI X X,et al.Evaluation of cytochrome P450 probe substrates commonly used by the pharmaceutical industry to study in vitro drug interactions .Drug Metab Dispos,2002,30(12): 1311-1319. WANG J,DING L,DU X,et al.Determination of ecabet and bismuth in human urine and study on their urinary excretion profiles .Chin Pharm J(中国药学杂志),2012,47(10): 825-830.
{{custom_fnGroup.title_cn}}
脚注
{{custom_fn.content}}
基金
国家“重大新药创制”科技重大专项资助项目(2009ZX09102-059)；江苏省2011年度普通高校研究生科研创新计划资助项目(CXZZ11_0811)
{{custom_fund}}
