Phytochemical-induced changes in gene expression of carcinogen-metabolizing enzymes in cultured human primary hepatocytes
Phytochemical-induced changes in gene expression of carcinogen-metabolizing enzymes in cultured human primary hepatocytes
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DOI：
10.1080/00498250412331285481
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发表时间：
2004-07-01
期刊：
影响因子：
1.8
通讯作者：
Eaton, DL
中科院分区：
文献类型：
--
作者：
Gross-Steinmeyer, K;Stapleton, PL;Eaton, DL
1.天然存在的化合物姜黄素（CUR），3，3 '-二吲哚甲烷（DIM），异黄腐酚（IXN），8-异戊二烯基柚皮素（8 PN），苯乙基异硫氰酸酯（PEITC）和萝卜硫素（SFN）保护动物免受化学诱导的肿瘤。假定的化学保护机制包括调节肝生物转化酶的表达。然而，很少有研究使用人类原代细胞作为测试模型。本研究探讨了这些植物化学物质对四种致癌相关酶-细胞色素P450（CYP）1A 1和1A 2、NAD（P）H：醌氧化还原酶（NQO 1）和谷胱甘肽S-转移酶A1（GSTA 1）-在新鲜分离的人肝细胞原代培养物中表达的影响.定量RT-PCR分析表明，CYP 1A 1被PEITC和DIM以剂量依赖性方式上调。DIM、IXN、8 PN和PEITC处理后，CYP 1A 2转录显著激活。DIM对CYP 1A 1（在50、25和10 μ M时分别为474、239和87倍）和CYP 1A 2（在50、25和10 μ M时分别为113、70和31倍）表现出显著有效的诱导反应，这在蛋白质水平上得到了半定量反映。NQO 1表达对PEITC（11 × 25 μ M）、DIM（4.5 × 50 μ M）和SFN（5 × 10 μ M）处理有反应。对GSTA 1转录没有明显影响.这些发现显示了这些植物化学物质对人类肝脏生物转化酶表达的新的和意想不到的选择，这些生物转化酶在化学诱导的致癌作用中起关键作用。
1. The naturally occurring compounds curcumin (CUR), 3,3'-diindolylmethane (DIM), isoxanthohumol (IXN), 8-prenylnaringenin (8PN), phenethyl isothiocyanate (PEITC) and sulforaphane (SFN) protect animals against chemically induced tumours. Putative chemoprotective mechanisms include modulated expression of hepatic biotransformation enzymes. However, few, if any, studies have used human primary cells as test models.2. The present study investigated the effects of these phytochemicals on the expression of four carcinogenesis-relevant enzymes - cytochrome P450 (CYP)1A1 and 1A2, NAD(P)H:quinone oxidoreductase (NQO1) and glutathione S-transferase A1 (GSTA1) - in primary cultures of freshly isolated human hepatocytes.3. Quantitative RT-PCR analyses demonstrated that CYP1A1 was up-regulated by PEITC and DIM in a dose-dependent manner. CYP1A2 transcription was significantly activated following DIM, IXN, 8PN and PEITC treatments. DIM exhibited a remarkably effective induction response of CYP1A1 (474-, 239- and 87-fold at 50, 25 and 10 muM, respectively) and CYP1A2 (113-, 70- and 31-fold at 50, 25 and 10 muM, respectively), that was semiquantitatively reflected in protein levels. NQO1 expression responded to PEITC (11 x at 25 muM), DIM (4.5 x at 50 muM) and SFN (5 x at 10 muM) treatments. No significant effects on GSTA1 transcription were seen.4. The findings show novel and unexpected elects of these phytochemicals on the expression of human hepatic biotransformation enzymes that play key roles in chemical-induced carcinogenesis.