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Effect of constitutive androstane receptor on the cytotoxicity of mitomycin C and 5-(aziridin-1-yl)-3-hydroxymethyl-1-methylindole-4,7-dione

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Author:
No author available
Journal Title:
ACTA PHARMACEUTICA SINICA
Issue:
4
DOI:
10.3321/j.issn:0513-4870.2007.04.005
Key Word:
丝裂霉素C;5-氮丙啶-3-羟甲基-1-甲基吲哚-4,7-二酮;细胞毒性;生物还原活性物;结构性雄烷受体;细胞色素P450

Abstract: 研究丝裂霉素C(MMC)及其衍生物5-氮丙啶-3-羟甲基-1-甲基吲哚-4,7-二酮[5-(aziridin-1-yl)-3-hydroxymethyl-1-methylindole-4,7-dione,629]的细胞毒性,以及结构性雄烷受体(constitutive androstane receptor,CAR)转染对其生物学效应的影响.将质粒mCAR/pCR3转染HepG2细胞,经G418耐药性筛选获得转染CAR的g2car细胞,以转染空载体pCR3(HepG2/pCR3)作为对照.用RT-PCR检测质粒和CYP2B6 mRNA的表达,用MTT法评价MMC和629对g2car细胞和HepG2细胞在有氧和乏氧条件下的细胞毒性.RT-PCR检测到CAR和CYP2B6 mRNA在g2car细胞中有表达,在HepG2细胞中无表达;此外,在乏氧情况下,MMC和629的细胞毒性比在有氧情况下均有所增加(P<0.05),并且转染CAR以后,两者的细胞毒性均增加,但对MMC的影响较明显(P<0.05),对629的影响不明显(P>0.05).提示CAR可在转录水平调节药物的代谢,提高药物的毒性;CYP2B6可以主要代谢MMC,但不主要代谢629.转染CAR基因可以增加细胞CYP2B6 mRNA的表达,并可引起MMC和629毒性的改变.

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