Snawder J E, Roe A L, Benson R W, Roberts D W
Division of Biochemical Toxicology, FDA, Jefferson, AR 72079.
Biochem Biophys Res Commun. 1994 Aug 30;203(1):532-9. doi: 10.1006/bbrc.1994.2215.
The effect of acetaminophen (APAP) dose on the cytochrome P450s responsible for its bioactivation was examined in control mice and mice treated with acetone to induce CYP2E1, or beta-napthaflavone to induce CYP1A2. In non-induced mice, 150 mg/kg APAP caused minimal hepatotoxicity and loss of CYP2E1- but not CYP1A2-dependent activity. In contrast, 400 mg/kg APAP was hepatotoxic and diminished both CYP2E1 and CYP1A2 activities. In acetone-pretreated mice, the 150 and 400 mg/kg APAP doses caused similar depletion of CYP2E1 activity and similar levels of covalent binding of APAP to liver proteins. In beta-napthaflavone-pretreated mice, CYP1A2 activity was decreased only by the high dose of APAP, and covalent binding was > 2-fold higher at the high APAP dose. The data indicate CYP2E1 is important in the bioactivation of APAP at the low dose with little additional contribution at the high dose, whereas CYP1A2 contributes more to the bioactivation and toxicity APAP at high doses.
在对照小鼠以及用丙酮诱导CYP2E1或用β-萘黄酮诱导CYP1A2的小鼠中，研究了对乙酰氨基酚（APAP）剂量对负责其生物活化的细胞色素P450的影响。在未诱导的小鼠中，150mg/kg的APAP引起最小的肝毒性以及CYP2E1依赖性活性丧失，但不影响CYP1A2依赖性活性。相比之下，400mg/kg的APAP具有肝毒性，且降低了CYP2E1和CYP1A2的活性。在丙酮预处理的小鼠中，150mg/kg和400mg/kg的APAP剂量导致CYP2E1活性的类似消耗以及APAP与肝脏蛋白共价结合的类似水平。在β-萘黄酮预处理的小鼠中，仅高剂量的APAP降低了CYP1A2活性，并且在高APAP剂量下共价结合增加了2倍以上。数据表明，CYP2E1在低剂量APAP的生物活化中起重要作用，在高剂量时贡献不大，而CYP1A2在高剂量APAP的生物活化和毒性中起更大作用。
