Iwata N, Minegishi K, Suzuki K, Ohno Y, Igarashi T, Satoh T, Takahashi A
Division of Xenobiotic Metabolism and Disposition, National Institute of Hygiene Sciences, Tokyo, Japan.
Biochem Pharmacol. 1993 Apr 22;45(8):1659-65. doi: 10.1016/0006-2952(93)90307-i.
We have demonstrated previously that musk xylene, a non-mutagenic carcinogen, is a novel and specific inducer of CYP1A2 in rats (Iwata et al., Biochem Biophys Res Commun 184: 149-153, 1992). In the present study, the effects of musk xylene (50, 100 or 200 mg/kg body weight, i.p., for 5 consecutive days) on both Phase I and Phase II metabolizing enzymes in rat liver were investigated further and more completely. Among the mixed-function oxidases monitored, 7-ethoxycoumarin deethylase and 7-pentoxyresorufin depentylase activities were increased at all dose levels from 1.6- to 1.7-fold and 2.6- to 3.1-fold, respectively. Benzo[a]pyrene hydroxylase activity was increased significantly at only the 200 mg/kg dose level of musk xylene (1.5-fold). Regarding Phase II enzymes, activities of both cytosolic DT-diaphorase and glutathione S-transferase (GST) were increased up to 2.0- to 2.4-fold by musk xylene in a dose-dependent manner. Western blot analysis revealed that the changes in these activities were caused by increases in the amounts of DT-diaphorase and GST Ya subunit. Microsomal UDP-glucoronyltransferase (UDPGT) activity assayed with p-nitrophenol as substrate was increased 1.6- to 2.0-fold. These results show that musk xylene induces both Phase I cytochrome P450 mixed-function oxidase (CYP1A2 specific) and Phase II metabolizing enzyme systems (DT-diaphorase, GST Ya subunit and UDPGT) in rat liver.
我们之前已经证明，麝香二甲苯作为一种非诱变致癌物，是大鼠中CYP1A2的新型特异性诱导剂（岩田等人，《生物化学与生物物理研究通讯》184: 149 - 153，1992）。在本研究中，进一步且更全面地研究了麝香二甲苯（50、100或200 mg/kg体重，腹腔注射，连续5天）对大鼠肝脏中I相和II相代谢酶的影响。在所监测的混合功能氧化酶中，7 - 乙氧基香豆素脱乙基酶和7 - 戊氧基试卤灵脱戊基酶活性在所有剂量水平下均增加，分别为1.6至1.7倍和2.6至3.1倍。仅在麝香二甲苯200 mg/kg剂量水平下，苯并[a]芘羟化酶活性显著增加（1.5倍）。关于II相酶，胞质DT - 黄递酶和谷胱甘肽S - 转移酶（GST）的活性均以剂量依赖方式被麝香二甲苯增加至2.0至2.4倍。蛋白质印迹分析表明，这些活性的变化是由DT - 黄递酶和GST Ya亚基量的增加引起的。以对硝基苯酚为底物测定的微粒体UDP - 葡萄糖醛酸基转移酶（UDPGT）活性增加了1.6至2.0倍。这些结果表明，麝香二甲苯诱导大鼠肝脏中的I相细胞色素P450混合功能氧化酶（特异性CYP1A2）和II相代谢酶系统（DT - 黄递酶、GST Ya亚基和UDPGT）。
