Iwata N, Suzuki K, Minegishi K, Kawanishi T, Hara S, Endo T, Takahashi A
Department of Forensic Medicine, Tokyo Medical College, Japan.
Eur J Pharmacol. 1993 Oct 1;248(3):243-50. doi: 10.1016/0926-6917(93)90051-q.
We characterized the inducing effects of two musk analogues, musk xylene and musk ambrette, on phase I and phase II drug-metabolizing enzymes in rat liver and compared their effects with 3-methylcholanthrene, isosafrole and 2(3)-tertbutylhydroxyanisole (BHA) at 0.1 mmol/kg dose level. Musk xylene and isosafrole increased more efficiently the metabolic activation of 2-amino-6-methyldipyrido[1,2-a:3',2'-d]imidazole (Glu-P-1) to mutagen than that of benzo(a)pyrene. Musk ambrette increased both the activation of Glu-P-1 and benzo(a)pyrene to the same extent. Western blot analyses revealed that musk xylene, musk ambrette, isosafrole and BHA induced more strongly cytochrome P450 1A2 (CYP1A2) in microsomes than CYP1A1. 3-Methylcholanthrene induced CYP1A1 in preference to CYP1A2. On the other hand, all drugs except for 3-methylcholanthrene did not show remarkable increases in phase II enzyme activities, such as DT-diaphorase, glutathione S-transferase and UDP-glucuronyltransferase, at 0.1 mmol/kg dose level. These results show that musk xylene, musk ambrette, isosafrole and BHA at the dose level used in this study possess the potency to induce CYP1A2 without remarkable induction of CYP1A1 and phase II enzyme activities as observed for 3-methylcholanthrene, although they have been considered to induce both phase I and phase II drug-metabolizing enzymes at higher doses.
我们研究了两种麝香类似物二甲苯麝香和葵子麝香对大鼠肝脏中Ⅰ相和Ⅱ相药物代谢酶的诱导作用，并将它们在0.1 mmol/kg剂量水平下的作用与3-甲基胆蒽、异黄樟素和2(3)-叔丁基对羟基茴香醚（BHA）进行了比较。二甲苯麝香和异黄樟素比苯并(a)芘更有效地提高了2-氨基-6-甲基二吡啶并[1,2-a:3',2'-d]咪唑（Glu-P-1）向诱变剂的代谢活化。葵子麝香在相同程度上提高了Glu-P-1和苯并(a)芘的活化。蛋白质免疫印迹分析显示，二甲苯麝香、葵子麝香、异黄樟素和BHA在微粒体中对细胞色素P450 1A2（CYP1A2）的诱导作用比对CYP1A1更强。3-甲基胆蒽优先诱导CYP1A1而非CYP1A2。另一方面，除3-甲基胆蒽外，所有药物在0.1 mmol/kg剂量水平下Ⅱ相酶活性（如DT-黄递酶、谷胱甘肽S-转移酶和UDP-葡萄糖醛酸基转移酶）均未显著增加。这些结果表明，本研究中使用的剂量水平的二甲苯麝香、葵子麝香、异黄樟素和BHA具有诱导CYP1A2的能力，而不像3-甲基胆蒽那样显著诱导CYP1A1和Ⅱ相酶活性。尽管它们在高剂量时被认为会诱导Ⅰ相和Ⅱ相药物代谢酶。
