Jaw S, Jeffery E H
Division of Nutritional Sciences, University of Illinois, Urbana-Champaign 61801.
Biochem Pharmacol. 1993 Aug 3;46(3):493-501. doi: 10.1016/0006-2952(93)90526-3.
The combination of caffeine with acetaminophen (APAP) is used widely in the treatment of headache. The effects of caffeine on APAP-induced hepatotoxicity and APAP bioactivation by liver microsomes from uninduced mice and from mice pretreated with various agents that induce cytochrome P450 were studied. When 1 mM caffeine was included, the rate of glutathione-APAP conjugate (GS-APAP) formation was increased significantly by 33 and 39% in microsomes from phenobarbital (PB)- and dexamethasone (DEX)-treated mice, respectively, whereas this parameter was decreased 39 and 12% by caffeine in microsomes from beta-naphthoflavone (beta NF)- and acetone-treated mice, respectively. A 5 mM concentration of caffeine increased GS-APAP formation by 47, 107 and 117% in microsomes from control, PB-, and DEX-treated mice, respectively, and decreased it 39 and 25% in microsomes from beta NF- and acetone-treated mice, respectively. Caffeine was a competitive inhibitor of APAP bioactivation in microsomes from beta NF- and acetone-treated mice. While caffeine increased APAP bioactivation in microsomes from uninduced, PB-, and DEX-treated mice, the apparent Km values for APAP were increased by caffeine, indicating that this enhancement was not due to a direct effect of caffeine on APAP binding to cytochrome P450 but may be due to an effect of caffeine on the substrate-enzyme complex. The variable effect of caffeine on APAP hepatotoxicity correlated with the effect of caffeine on APAP bioactivation by liver microsomes, regardless of pretreatment. Lack of correlation of aminopyrine N-demethylase, but good correlation of erythromycin N-demethylase activity with the extent of caffeine enhancement of APAP bioactivation following PB or DEX treatment suggests that a murine P450 subfamily similar to the rat P450 3A subfamily may be the candidate in mediating the stimulatory effect of caffeine on APAP bioactivation and APAP-induced hepatotoxicity.
咖啡因与对乙酰氨基酚（APAP）联合用药在头痛治疗中被广泛应用。本研究探讨了咖啡因对APAP诱导的肝毒性以及来自未诱导小鼠和经各种诱导细胞色素P450的药物预处理小鼠的肝微粒体对APAP生物活化的影响。当加入1 mM咖啡因时，苯巴比妥（PB）和地塞米松（DEX）处理小鼠的微粒体中谷胱甘肽-APAP共轭物（GS-APAP）的形成速率分别显著增加33%和39%，而在β-萘黄酮（βNF）和丙酮处理小鼠的微粒体中，该参数分别被咖啡因降低了39%和12%。5 mM浓度的咖啡因使对照、PB和DEX处理小鼠的微粒体中GS-APAP的形成分别增加了47%、107%和117%，而在βNF和丙酮处理小鼠的微粒体中分别降低了39%和25%。在βNF和丙酮处理小鼠的微粒体中，咖啡因是APAP生物活化的竞争性抑制剂。虽然咖啡因增加了未诱导、PB和DEX处理小鼠微粒体中APAP的生物活化，但APAP的表观Km值因咖啡因而增加，这表明这种增强并非由于咖啡因对APAP与细胞色素P450结合的直接作用，而可能是由于咖啡因对底物-酶复合物的作用。无论预处理如何，咖啡因对APAP肝毒性的可变影响与咖啡因对肝微粒体APAP生物活化的影响相关。氨基比林N-脱甲基酶缺乏相关性，但红霉素N-脱甲基酶活性与PB或DEX处理后咖啡因增强APAP生物活化的程度具有良好的相关性，这表明类似于大鼠P450 3A亚家族的小鼠P450亚家族可能是介导咖啡因对APAP生物活化和APAP诱导肝毒性刺激作用的候选者。
