血府逐瘀汤对大鼠肝组织内CYPs,UGTs和GSTs基因表达的影响

Effect of Xuefu Zhuyu Decoction on Gene Expression of CYPs,UGTs and GST sin Liver Tissues of Rats

目的:研究血府逐瘀汤对大鼠肝组织内药物代谢酶细胞色素P450(CYPs,cytochrome P450),谷胱甘肽-S-转移酶GSTs,glutathione S transferase)和尿甘二磷酸葡糖醛酸转移酶(UGTs,UDP-glucuronosyl transferase)基因表达的影响。方法:将25只大鼠随机分为5组,每组5只。大鼠按3.51,7.02,14.04 g·kg-1分别ig给予血府逐瘀汤水提物,空白组给等体积纯净水,连续给药15 d,苯巴比妥钠于第13天按80 mg·kg-1腹腔注射,连续3 d。取200 mg左右肝脏,用逆转录-实时荧光定量PCR法检测肝组织内的CYP基因CYP1A1,CYP1A2,CYP2B1,CYP2C11,CYP2E1,CYP3A1,CYP3A2,CYP4A1,CYP7A1,CYP17A1,CYP27A1,GST基因GSTA2,GSTM1,GSTp1和UGT基因UGT1A1,UGT2B1的表达情况。结果:与空白组比较,苯巴比妥钠组(阳性组)可明显诱导CYP2B1,CYP3A1,CYP3A2,GSTA2和UGT2B1基因表达(84.57,5.44,5.11,7.76,13.27倍,P<0.01);血府逐瘀汤3.51,7.02 g·kg-1分别诱导GSTA2和CYP1A1的基因表达(1.54倍,P<0.05;57.92倍,P<0.05);14.04 g·kg-1明显抑制CYP2C11的基因表达(55%,P<0.05);3.51,7.02,14.04 g·kg-13个剂量对GSTM1有明显的抑制作用(53%,55%,51%,P<0.05);血府逐瘀汤对CYP1A2,CYP2B1,CYP2E1,CYP3A1,CYP3A2,CYP4A1,CYP7A1,CYP17A1,CYP27A1,GSTp1,UGT1A1和UGT2B1的基因表达无明显影响。结论:血府逐瘀汤可明显诱导CYP1A1,GSTA2基因的表达,对CYP2C11,GSTM1的基因有明显的抑制作用,而对其余的亚型无显著影响。提示临床上与CYP1A1及CYP2C11的底物合用时,要注意药物代谢性相互作用,且其可能参与肝脏对毒物、致癌物以及其他物质的解毒和排泄,对多种恶性肿瘤的发生可能起到一定的作用。

Objective： To examine the effects of Xuefu Zhuyu decoction （XFZYD） on the expression of cytochrome P450 （CYPs） genes,glutathione S-transferase （GSTs） genes and UDP-glucuronosyl transferase （UGTs） genes in liver tissues of male Sprague-Dawley rats. Method： Twenty-five rats were divided randomly into 5 groups,5 animals each. Three active dose groups,which were administered with XFZYD by gastrogarage for 15 days at the dose of 3.51,7.02 and 14.04 g kg-1,respectively. The control group and positive group received the same volume of water per kg body weight. From 13th day,the positive group received Phenobarbital sodium at the dose of 80 mg kg-1 by peritomeal injection for 3 days. About 200 mg livers were removed,the levels of genes expression of CYP1A1,CYP1A2,CYP2B1,CYP2E1,CYP2C11,CYP3A1,CYP3A2,CYP4A1,CYP7A1,CYP17A1,CYP27A1,GSTA2,GSTM1,GSTp1,UGT1A1 and UGT2B1 in liver tissues of rats were examined by Quantitative real-time reverse-transcription polymerase chain reaction （quantitative real time RT-PCR） assays. Result： Compared with the contro group l,phenobarbital sodium （the positive group） significantly increased mRNA expressions of CYP2B1,CYP3A1,CYP3A2,GSTA2 and UGT2B1 （84.57-fold,5.44-fold,5.11-fold,7.76-fold,13.27-fold,P〈0.01,respectively）. CYP1A1 （57.92-fold,P〈0.01） and GSTA2 （1.54-fold P〈0.05） were dramatically induced by XFZYD at the dose of 7.02, 3.51 g kg-1,respectively. While CYP2C11 （55%,P〈0.05） was significantly inhibited by XFZYD at the dose of 14.04 g kg-1,a inhibitory tendency was found on expression of GSTM1 （P〈0.05） at the dose of 3.51,7.02, 14.04 g kg-1 （53%,55%,51%,respectively）,however,XFZYD had no significant effect on the expression of CYP1A2,CYP2B1,CYP2E1,CYP3A1,CYP3A2,CYP4A1,CYP7A1,CYP17A1,CYP27A1,GSTp1,UGT1A1 and UGT2B1. Conclusion： XFZYD can significantly induced the expression of CYP1A1 and GSTA2 gene,but significantly inhibited CYP2C11 and GSTM1 genes,which indicated that when XFZYD is administrated with the substrate of CYP1A1 and CYP2C11,more attention should be paid on drug interactions,XFZYD may affect detoxication and excretion of toxicants,acarcinogens and other substances,and may play a role in the occurrence of malignant tumor.