Kalhorn T F, Lee C A, Slattery J T, Nelson S D
Department of Pharmaceutics, University of Washington, Seattle.
J Pharmacol Exp Ther. 1990 Jan;252(1):112-6.
The effect of caffeine, theophylline and theobromine on acetaminophen-induced hepatotoxicity was evaluated in uninduced, 3-methylcholanthrene- and phenobarbital-induced adult male Sprague-Dawley rats. The methylxanthines themselves did not cause hepatotoxicity in any induction state. In 3-methylcholanthrene-induced rats, each methylxanthine afforded protection (in varying degrees) against acetaminophen-induced hepatotoxicity as reflected by serum alanine aminotransferase and liver histopathology determined 24 hr after acetaminophen administration. However, in phenobarbital-induced rats, caffeine and theophylline substantially potentiated the hepatotoxicity of acetaminophen whereas theobromine had no effect. Hepatic glutathione (GSH) was determined in rats that received caffeine 4 hr after acetaminophen or vehicle. Acetaminophen alone substantially depleted hepatic GSH in each induction state, whereas caffeine depleted hepatic GSH in uninduced and phenobarbital-induced, but not in 3-methylcholanthrene-induced rats. In rats that received both caffeine and acetaminophen together, hepatic GSH depletion was greater than in rats that received acetaminophen only. The effect of caffeine on hepatic GSH is most likely due to a decrease in core body temperature. The most likely mechanisms for the effects observed are 1) inhibition of acetaminophen reactive metabolite formation in 3-methylcholanthrene-induced animals by each of the methylxanthines, and 2) activation of the phenobarbital-inducible forms of cytochrome(s) P-450 toward formation of acetaminophen reactive metabolites by caffeine and theophylline, but not theobromine.
在未诱导、经3-甲基胆蒽和苯巴比妥诱导的成年雄性Sprague-Dawley大鼠中，评估了咖啡因、茶碱和可可碱对乙酰氨基酚诱导的肝毒性的影响。甲基黄嘌呤本身在任何诱导状态下均未引起肝毒性。在经3-甲基胆蒽诱导的大鼠中，每种甲基黄嘌呤（程度不同）都对乙酰氨基酚诱导的肝毒性提供了保护，这一点通过乙酰氨基酚给药24小时后测定的血清丙氨酸转氨酶和肝脏组织病理学得以体现。然而，在经苯巴比妥诱导的大鼠中，咖啡因和茶碱显著增强了乙酰氨基酚的肝毒性，而可可碱则没有影响。在乙酰氨基酚或赋形剂给药4小时后接受咖啡因的大鼠中测定了肝脏谷胱甘肽（GSH）。单独使用乙酰氨基酚在每种诱导状态下均使肝脏GSH大量耗竭，而咖啡因在未诱导和经苯巴比妥诱导的大鼠中使肝脏GSH耗竭，但在经3-甲基胆蒽诱导的大鼠中则没有。在同时接受咖啡因和乙酰氨基酚的大鼠中，肝脏GSH的耗竭程度大于仅接受乙酰氨基酚的大鼠。咖啡因对肝脏GSH的影响很可能是由于核心体温降低所致。观察到的这些效应最可能的机制是：1）在经3-甲基胆蒽诱导的动物中，每种甲基黄嘌呤均抑制乙酰氨基酚活性代谢物的形成；2）咖啡因和茶碱激活苯巴比妥诱导型细胞色素P-450形成乙酰氨基酚活性代谢物，但可可碱则没有。
