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目的研究辛伐他汀(simvastatin,SV)对大鼠肝脏药物代谢酶活性的影响。方法大鼠口服给予SV,qd×7,超速离心法分离肝微粒体,一氧化碳示差光谱法测定细胞色素P450(CYP)含量,以红霉素、苯胺、CDNB、利尿酸、7-羟基-4-甲基香豆素和对羟基联苯为底物分别测定肝微粒体红霉素脱甲基酶(CYP3A4)、苯胺羟化酶(CYP2E1)、谷胱甘肽-S-转移酶(glutathione Stransferase,GST)及其π亚型(πGST)、尿苷二磷酸葡萄糖醛酸转移酶(uridine diphosphoglucuronyl transferase,UGT1和UGT2)活性。结果大鼠口服给予SV可明显降低大鼠肝微粒体CYP含量及CYP3A4活性,对CYP2E1则没有显明影响。同时,SV则可显著增高大鼠肝微粒体GST、πGST及UGT1和UGT2活性。结论SV可降低大鼠肝微粒体CYP3A4活性,而增高肝微粒体Ⅱ相代谢酶的活性。
Objective To study the effects of simvastatin (SV) on hepatic drug metabolism enzyme activity in rats. Methods The rat was orally administrated with SV, qd × 7, and the microsomes of liver were isolated by ultracentrifugation. The content of cytochrome P450 (CYP) was determined by carbon monoxide differential spectroscopy. The contents of CYP in erythromycin, aniline, CDNB, Methylcoumarin and p-hydroxybiphenyl were used as substrates to determine the changes of microsomal erythromycin demethylase (CYP3A4), aniline hydroxylase (CYP2E1), glutathione-S-transferase GST) and its π subtype (πGST), uridine diphosphoglucuronyl transferase (UGT1 and UGT2) activity. Results Oral administration of SV significantly reduced the CYP content and CYP3A4 activity in rat liver microsomes, but did not affect CYP2E1 significantly. At the same time, SV can significantly increase the rat liver microsomal GST, πGST and UGT1 and UGT2 activity. Conclusion SV can reduce the activity of CYP3A4 in rat liver microsomes and increase the activity of phase Ⅱ metabolic enzymes in liver microsomes.