van Maanen J M, de Vries J, Pappie D, van den Akker E, Lafleur V M, Retèl J, van der Greef J, Pinedo H M
Cancer Res. 1987 Sep 1;47(17):4658-62.
The antitumor agent VP-16-213 is oxidatively O-demethylated by rat liver microsomes and purified rat liver microsomal cytochrome P-450. 3-Methylcholanthrene can quantitatively induce O-demethylation of VP-16-213. The Km and Vmax values for O-demethylation by noninduced, phenobarbital-, and 3-methylcholanthrene-induced rat liver microsomes were found to be 130, 600, and 160 microM and 8.5, 11.8, and 15.6 nmol H2CO/min X mg protein, respectively. Mass spectrometric comparison of the product of O-demethylation of VP-16-213 with the synthetic metabolite resulted in identification of the orthodihydroxy derivative. In studies on the biological activity of the orthodihydroxy derivative, it was found to inactivate single- and double-stranded phiX174 DNA, to bind to calf thymus DNA and to be highly toxic against chinese hamster ovary cells.
抗肿瘤药物VP - 16 - 213可被大鼠肝微粒体和纯化的大鼠肝微粒体细胞色素P - 450氧化O - 去甲基化。3 - 甲基胆蒽可定量诱导VP - 16 - 213的O - 去甲基化。未诱导、苯巴比妥诱导和3 - 甲基胆蒽诱导的大鼠肝微粒体进行O - 去甲基化的Km值和Vmax值分别为130、600和160微摩尔，以及8.5、11.8和15.6纳摩尔H2CO/分钟×毫克蛋白。对VP - 16 - 213的O - 去甲基化产物与合成代谢物进行质谱比较，鉴定出邻二羟基衍生物。在对邻二羟基衍生物的生物活性研究中，发现它可使单链和双链φX174 DNA失活，与小牛胸腺DNA结合，并对中国仓鼠卵巢细胞具有高毒性。
