Yamagata S, Ohmori S, Suzuki N, Yoshino M, Hino M, Ishii I, Kitada M
Drug Metab Dispos. 1998 Apr;26(4):379-82.
The N-demethylation of dacarbazine in liver microsomes was significantly increased by treatment of rats with beta-naphthoflavone, dexamethasone, or phenobarbital. However, the extent of increase in the N-demethylation observed in beta-naphthoflavone-treated rats was much greater than that observed in dexamethasone-treated rats. A good correlation between N-demethylation of dacarbazine and O-deethylation of phenacetin was observed when a low concentration of phenacetin was used. Furthermore, the activity of dacarbazine N-demethylase in rat liver microsomes was highly correlated with the amounts of CYP protein immunochemically determined with anti-rat CYP1A2 antibodies. In addition, antibodies to rat CYP1A2, and furafylline and alpha-naphthoflavone, which are known inhibitors of CYP1A enzymes, exhibited inhibitory effects on dacarbazine N-demethylation. These results indicated that CYP1A enzymes may be responsible for N-demethylation of dacarbazine in rat liver microsomes.
用β-萘黄酮、地塞米松或苯巴比妥处理大鼠后，肝微粒体中达卡巴嗪的N-去甲基化显著增加。然而，在β-萘黄酮处理的大鼠中观察到的N-去甲基化增加程度远大于在地塞米松处理的大鼠中观察到的增加程度。当使用低浓度非那西丁时，观察到达卡巴嗪的N-去甲基化与非那西丁的O-去乙基化之间有良好的相关性。此外，大鼠肝微粒体中达卡巴嗪N-去甲基酶的活性与用抗大鼠CYP1A2抗体免疫化学测定的CYP蛋白量高度相关。此外，大鼠CYP1A2抗体以及已知的CYP1A酶抑制剂呋拉茶碱和α-萘黄酮对达卡巴嗪的N-去甲基化有抑制作用。这些结果表明，CYP1A酶可能负责大鼠肝微粒体中达卡巴嗪的N-去甲基化。
