NQO1介导的丹参酮IIA的代谢转化与细胞毒(英文)

NQO1-mediated biotransformation determines the cytotoxicity of tanshinone IIA

目的:确证丹参酮 IIA 的细胞毒依赖于 NAD(P)H 醌氧化还原酶 (NQO1)这一假设。方法:首先进行 MTT试验考察丹参酮 IIA 在一系列具有不同 NQO1 酶活的细胞株的细胞毒, 并考察 NQO1 的特异性抑制剂双香豆素对丹参酮 IIA 细胞毒的逆转来确证丹参酮 IIA 的细胞毒是依赖于 NQO1 的。然后在具有较强丹参酮 IIA 细胞毒的 HepG2 细胞中考察了丹参酮 IIA的生物转化情况, 并考察了双香豆素对丹参酮 IIA 生物转化情况影响。结果:丹参酮 IIA 的细胞毒与细胞株的 NQO1 酶活呈正相关。双香豆素能够逆转丹参酮 IIA 的细胞毒作用, 同时也能抑制丹参酮 IIA 在 HepG2 细胞毒的生物转化。结论:NQO1 是丹参酮 IIA 发挥抗肿瘤效应的首要靶点, 通过抑制 NQO1 双香豆素能够减少丹参酮 IIA 向儿茶酚中间体的转化, 从而打破丹参酮 II在 NQO1 介导下发生还原-自氧化-还原循环, 减少活性氧自由基的产生, 而减少丹参酮 IIA 的细胞毒作用。由此证明, 丹参酮 IIA的细胞毒是由 NQO1-介导其生物转化过程而产生的。

AIM： To confirm the hypothesis that the cytotoxicity of tanshinone IIA （TSA） is dependent on NAD（P）H quinone oxidoreductase （NQO1）-mediated biotransformation. METHOD： MTT assay in a series of cell lines with diverse NQO1 enzyme activity in the presence or absence of the typical NQO1 inhibitor dicoumarol （DIC） was applied to test the NQOl-dependent cytotoxic- ity of TSA. Then the NQO1-dependent biotransformation of TSA in HepG2 ceils was investigated with or without DIC. RESULTS： TSA＇s cytotoxicity is positively correlated with NQO1 enzyme activity in the cell lines. DIC could reverse the cytotoxicity of TSA in HepG2 cells with the highest NQO1 enzyme. DIC could also inhibit the biotransformation of TSA in HepG2 cells. CONCLUSION： By inhibiting NQO1, DIC could inhibit the biotransformation of TSA into a catechol intermediate in HepG2 cells, resulting in distur- bance of the redox cycle of TSA, thereby reducing the cytotoxicity of TSA. In summary, NQO 1-mediated biotransformation determines the cytotoxicity of Tanshinone IIA.