Mahéo K, Morel F, Langouët S, Kramer H, Le Ferrec E, Ketterer B, Guillouzo A
INSERM U456, Détoxication et Réparation Tissulaire, Faculté des Sciences Pharmaceutiques et Biologiques, Université de Rennes I, France.
Cancer Res. 1997 Sep 1;57(17):3649-52.
The isothiocyanate sulforaphane (SF) is thought to be a potential chemoprotective agent. Its effects on Phase I and Phase II enzymes of carcinogen metabolism in primary cultures of rat and human hepatocytes have been investigated. Northern blot analyses of rat hepatocytes showed a dose-dependent induction of mRNAs for rat glutathione S-transferases (rGSTs) A1/A2 and P1 but not M1. This was associated with enhanced levels of not only rGSTA1, A2, A4, A5, and P1 but also of rGSTs M1 and M2. On the other hand, the enzyme activities in rat hepatocytes associated with cytochromes P-450 (CYPs) 1A1 and 2B1/2, namely ethoxyresorufin-O-deethylase and pentoxyresorufin-O-dealkylase, respectively, were decreased in a dose-dependent manner. In SF-treated human hepatocytes, hGSTA1/2 but not hGSTM1 mRNAs were induced, and the expression of CYP1A2 was unaffected, whereas the expression of CYP3A4, the major CYP in human liver, was markedly decreased at both mRNA and activity levels. These observations demonstrate that in intact human and rat hepatocytes, SF may both induce a number of GSTs and cause enzyme inhibition of some but not all CYPs and, in the case of CYP3A4, inhibit both its enzyme activity and its expression.
异硫氰酸酯萝卜硫素（SF）被认为是一种潜在的化学保护剂。已对其在大鼠和人原代肝细胞中对致癌物代谢的Ⅰ相和Ⅱ相酶的影响进行了研究。对大鼠肝细胞的Northern印迹分析显示，大鼠谷胱甘肽S-转移酶（rGSTs）A1/A2和P1的mRNA呈剂量依赖性诱导，但M1无此现象。这不仅与rGSTA1、A2、A4、A5和P1水平升高有关，还与rGSTs M1和M2水平升高有关。另一方面，大鼠肝细胞中与细胞色素P-450（CYPs）1A1和2B1/2相关的酶活性，即乙氧异羟肟酸-O-脱乙基酶和戊氧异羟肟酸-O-脱烷基酶，分别以剂量依赖性方式降低。在经SF处理的人肝细胞中，hGSTA1/2的mRNA被诱导，但hGSTM1的mRNA未被诱导，CYP1A2的表达未受影响，而人肝脏中的主要CYP即CYP3A4的表达在mRNA和活性水平上均显著降低。这些观察结果表明，在完整的人和大鼠肝细胞中，SF可能既诱导多种GSTs，又对部分而非全部CYPs产生酶抑制作用，就CYP3A4而言，既抑制其酶活性又抑制其表达。
