Lee C A, Thummel K E, Kalhorn T F, Nelson S D, Slattery J T
Department of Pharmaceutics, University of Washington, Seattle 98195.
Drug Metab Dispos. 1991 Mar-Apr;19(2):348-53.
Caffeine has previously been shown to diminish or potentiate acetaminophen (APAP) hepatotoxicity in rats, depending on induction state. To elucidate the P-450 forms involved in these divergent effects, rat liver microsomes, prepared after pretreatment with various inducers, were used to examine the effect of caffeine on N-acetyl-p-benzoquinone imine (NAPQI) formation. The addition of caffeine to incubations with 3-methylcholanthrene (MC)-induced microsomes resulted in a biphasic effect on the formation of NAPQI. A 43% decrease in NAPQI formation was observed as caffeine concentration was increased from 0 to 0.5 mM; however, NAPQI formation was accelerated as caffeine concentration increased, exceeding the control (no caffeine) value, at caffeine concentrations greater than 2.5 mM. Incubations with purified P-450IA1 showed that as caffeine concentration increased from 0 to 5 mM, a 50% inhibition was observed with no evidence of acceleration. In contrast to MC microsomes, the addition of caffeine to incubations with uninduced and phenobarbital-induced adult rat microsomes resulted in a marked (3- to 4-fold) acceleration of NAPQI formation with no evidence of inhibition. Caffeine (5 mM) also accelerated NAPQI formation in microsomes isolated from diabetic rats, but to a substantially lesser extent (120%), suggesting a modest (if any) effect on P-450IIE1, a form previously shown to form NAPQI from APAP. Interestingly, caffeine caused a 3- to 4-fold increase in NAPQI formation by juvenile male and female rat microsomes, but no activation was observed with adult female rat microsomes. These results suggested that caffeine activated a member of the cytochrome P-450IIIA subfamily.(ABSTRACT TRUNCATED AT 250 WORDS)
先前的研究表明，咖啡因可减轻或增强大鼠对乙酰氨基酚（APAP）的肝毒性，这取决于诱导状态。为了阐明参与这些不同效应的P-450形式，使用经各种诱导剂预处理后制备的大鼠肝微粒体来研究咖啡因对N-乙酰对苯醌亚胺（NAPQI）形成的影响。向与3-甲基胆蒽（MC）诱导的微粒体的孵育体系中添加咖啡因，对NAPQI的形成产生了双相效应。当咖啡因浓度从0增加到0.5 mM时，观察到NAPQI形成减少了43%；然而，当咖啡因浓度增加时，NAPQI的形成加速，在咖啡因浓度大于2.5 mM时超过了对照（无咖啡因）值。用纯化的P-450IA1进行孵育表明，随着咖啡因浓度从0增加到5 mM，观察到50%的抑制作用，没有加速的迹象。与MC微粒体相反，向未诱导和苯巴比妥诱导的成年大鼠微粒体的孵育体系中添加咖啡因，导致NAPQI形成显著加速（3至4倍），没有抑制的迹象。咖啡因（5 mM）也加速了从糖尿病大鼠分离的微粒体中NAPQI的形成，但程度要小得多（120%），这表明对P-450IIE1有适度（如果有的话）的影响，P-450IIE1是先前显示可从APAP形成NAPQI的一种形式。有趣的是，咖啡因使幼年雄性和雌性大鼠微粒体的NAPQI形成增加了3至4倍，但成年雌性大鼠微粒体未观察到激活作用。这些结果表明，咖啡因激活了细胞色素P-450IIIA亚家族的一个成员。（摘要截短至250字）
