青蒿素类药物对大鼠肝内组成型雄烷受体和CYP2B的诱导作用  

Inductive effects of artemisinin-based antimalarials on nuclear receptor CAR and CYP2B in rats liver

作　　者：王向[1] 白克华[1] 孙坤[1] 张淑秋[1] 

机构地区：[1]山西医科大学药学院临床药学教研室,太原030001

出　　处：《中国药物与临床》2010年第8期849-851,共3页Chinese Remedies & Clinics

基　　金：国家自然科学基金(30973589);山西省回国留学人员科研资助项目(2009-47)

摘　　要：目的探讨青蒿素(ART)和双氢青蒿素(DHA)对大鼠肝内组成型雄烷受体(CAR)和细胞色素P450s(CYP450s)的诱导作用。方法 SD大鼠随机分为8组:口服ART诱导组(80mg·kg-1·d-1);口服DHA诱导组(10mg·kg-1·d-1);口服溶剂对照组;静脉注射ART诱导组(16mg·kg-1·d-1);静脉推注DHA诱导组(5mg·kg-1·d-1);静脉推注溶剂(ART)对照组;静脉推注溶剂(DHA)对照组;空白对照组。连续给药5d,第6天处死大鼠,取肝组织,采用实时荧光定量聚合酶链反应方法检测各组大鼠肝内核受体和CYP450s mRNA水平。结果相比溶剂对照组和空白对照组,口服ART诱导组大鼠CAR和CYP2B1 mRNA水平显著增加(P<0.01),口服DHA诱导组中CYP2B1 mRNA水平显著增加(P<0.01),而静脉推注ART和DHA诱导组大鼠CAR及CYP450s mRNA水平与对照组间差异无统计学意义。结论多剂量口服青蒿素类药物很可能激活核受体CAR,进而上调CYP2B mRNA水平,从而增加自身代谢。而多剂量静脉注射ART和DHA对核受体CAR及CYP450s mRNA水平均没有影响,说明青蒿素类药物对于CYP450s的诱导作用基于首过代谢。Objective To investigate the inductive effects of artemisinin （ART） and dihydroartemisinin （DHA） on nuclear receptors and drug-metabolizing CYP450s in rats liver. Methods SD rats were randomly divided into eight groups： oral ART group （80 mg·kg^-1·d^-1 for 5 days）, oral DHA group （10 mg·kg^-1·d^-1 for 5 days）, oral vehicle control group, intravenous ART group （6 mg·kg^-1·d^-1 for 5 days）, intravenous DHA group （5 mg·kg^-1·d^-1 for 5 days）, intravenous vehicle （ART） control group, intravenous vehicle （DHA） control group and blank control group. All rats were sacrificed and harvested for livers at 24 hours after the last dose. The mRNA expression of nuclear receptors and CYP450s in rat liver was determined by SYBR green real-time quantitative PCR. Results Compared to vehicle control group and blank control group, mRNA expression of both CYP2B1 and CAR in oral ART treated rats was in- creased significantly （P〈0.01）. CYP2B1 mRNA expression was also significantly increased in oral DHA rats （P〈0.01）. Yet ART or DHA-intravenously treated rats did not show significant changes in mRNA expression of both nuclear receptor and CYP450s, compared to control groups. Conclusion Multiple oral doses of artemisinin-based drugs appeared to activate nuclear receptor CAR which in turn up-regulated CYP2B1 mRNA expression and promote metabolism of the drugs, whereas multiple intravenous doses of ART or DHA had no evident inductive effects on metabolism enzymes. This suggested that inductive action of artemisinin-based drugs may be based on first-pass effect.

关 键 词：青蒿素类 雄酮 细胞色素类 

分 类 号：R285.5[医药卫生—中药学]