Yamazaki H, Inui Y, Wrighton S A, Guengerich F P, Shimada T
Osaka Prefectural Institute of Public Health, Japan.
Carcinogenesis. 1995 Sep;16(9):2167-70. doi: 10.1093/carcin/16.9.2167.
Recent studies indicate that cytochrome P450 (P450) 3A4 plays important roles in the activation of procarcinogens such as aflatoxin B1 and sterigmatocystin, as well as in the oxidation of a number of structurally diverse chemicals and endogenous compounds. Since P450 3A5 has been reported to be present at significant levels in liver microsomes in approximately 25% of human adults, we examined and compared the role of P450 3A4 and 3A5 in procarcinogen activation in humans. Immunoblot experiments with liver microsomes from 60 human samples suggested that 4/30 Japanese and 4/30 Caucasians contained considerable levels of P450 3A5, although P450 3A4 could be determined at relatively high levels in all of the human samples examined. Good correlation was observed between P450 3A4, but not P450 3A5, levels versus activation of aflatoxin B1 and stergmatocystin in these human samples. Comparisons of the activation of procarcinogens in reconstituted monooxygenase systems containing modified P450 3A4 and 3A5 enzymes expressed in Escherichia coli were carried out in Salmonella typhimurium TA1535/pSK1002 or NM2009 tester strain for genotoxicity assay, and it was found that P450 3A4 had similar activities to or higher rates than P450 3A5 for the 24 procarcinogens tested.
最近的研究表明，细胞色素P450（P450）3A4在黄曲霉毒素B1和杂色曲霉素等前致癌物的激活以及许多结构各异的化学物质和内源性化合物的氧化过程中发挥着重要作用。由于据报道，约25%的成年人体内肝脏微粒体中P450 3A5含量显著，我们研究并比较了P450 3A4和3A5在人类前致癌物激活中的作用。对60份人类样本的肝脏微粒体进行免疫印迹实验表明，尽管在所检测的所有人类样本中都能检测到相对较高水平的P450 3A4，但30名日本人中有4名以及30名高加索人中有4名含有相当水平的P450 3A5。在这些人类样本中，观察到P450 3A4水平与黄曲霉毒素B1和杂色曲霉素的激活之间存在良好的相关性，但P450 3A5水平与它们的激活之间没有相关性。在鼠伤寒沙门氏菌TA1535/pSK1002或NM2009测试菌株中进行了基因毒性测定，对含有在大肠杆菌中表达的修饰P450 3A4和3A5酶的重组单加氧酶系统中前致癌物的激活进行了比较，结果发现，对于所测试的24种前致癌物，P450 3A4的活性与P450 3A5相似或更高。
