摘要
目的探究昆明种小鼠细胞色素氧化酶1A1(CYP1A1)的昼夜节律、性别差异以及对肝毒物毒性变化的影响。方法昆明小鼠在环境控制的SPF饲养室内适应性饲养2周后,于06:00,10:00,14:00,18:00,22:00和次日02:00处死取肝,用逆转录PCR方法检测24h内核激素孤儿受体α(Rev-erbα),时钟基因(Per)1,Per2和CYP1A1,CYP1A2及其调控核受体基因AhR的表达。另取小鼠于6:00和18:00 ip给予对乙酰氨基酚500mg·kg-1,12h后检测血清中丙氨酸转氨酶(ALT)和天冬氨酸转氨酶(AST)活性。结果细胞色素氧化酶基因CYP1A1,CYP1A2及其调节基因AhR在18:00左右表达最高,且雌鼠的表达高于雄鼠,在6:00左右表达最低,表达峰谷差为4～7倍,其节律变化的差异与Rev-erbα,Per1,Per2的节律差异大致相符。与此节律相对应,对乙酰氨基酚引起的肝毒性在18:00给药高于6:00给药。结论昆明种小鼠细胞色素氧化酶CYP1A1基因表达存在昼夜节律及性别差异,该差异可影响肝毒物如对乙酰氨基酚的代谢和毒性。
OBJECTIVE To examine circadian rhythm and sex variation of cytochrome P-450 1A1（CYP1A1） and aryl hydrocarbon receptor（AhR） expression in the liver of Kunming（KM） mice.METHODS Adult KM mice were maintained in the SPF-grade animal facilities for 2 weeks,and livers were collected every 4 h during the 24 h period.Total RNA was isolated,purified,and subjected to reverse transcription（RT）-PCR analysis for expression of CYP1A1,AhR and clock genes.Paracetamol 500 mg·kg-1 was ip given another 20 mice at 6：00 and 18：00,and alanine aminotransferase（ALT） and aspartate aminotransferase（AST） were determined.RESULTS The expressions of AhR and AhR-regulated CYP1A11 and CYP1A12 peaked about 18：00 pm and reached the nadir about 6：00 am.Sex-differences for AhR（6-fold for females and 7-fold for males）,CYP1A11（4-fold for females and 29-fold for males）,and CYP1A12（3-fold for females and 5-fold for maes） were also evident.The circadian variation of CYP1A1 and AhR resembled the clock genes Rev-erbα,Per1 and Per2.Circadian rhythm of CYP1A1 expression influenced the hepatotoxicity of paracetamol,which is bioactivated by CYP1A1.CONCLUSION Circadian rhythm and sex variation of CYP1A1 and AhR were evident in the liver of KM mice,which could impact the pharmacology and toxicology of drugs such as paracetamol.
出处
《中国药理学与毒理学杂志》
CAS
CSCD
北大核心
2013年第3期406-410,共5页
Chinese Journal of Pharmacology and Toxicology
基金
基金项目:贵州省科技厅国际合作基金(2009-70019)
贵州省科技厅药物代谢动力学平台项目(黔科2008-002)
贵州省研究生教育创新基地(023)~~
