Buters J T, Zysset T, Reichen J
Department of Clinical Pharmacology, University of Berne, Switzerland.
Biochem Pharmacol. 1993 Sep 14;46(6):983-91. doi: 10.1016/0006-2952(93)90662-g.
Antipyrine metabolism depends on at least three isoenzymes of cytochrome P450 forming the main metabolites 3-OH-, 4-OH- and norantipyrine. We investigated to what extent antipyrine clearance and metabolite formation are impaired in two models of liver cirrhosis in the rat, namely micronodular cirrhosis induced by chronic exposure to phenobarbital/CCl4 and biliary cirrhosis induced by bile duct ligation. Salivary antipyrine clearance was decreased to a similar extent in cirrhosis induced by CCl4 and bile duct ligation (-35%). Clearance for production of 3-OH-antipyrine was decreased in both models, while 4-hydroxylation was maintained. Metabolic clearance of both 3-OH-antipyrine and 4-OH-antipyrine in vivo correlated with their clearance in vitro (r = 0.658 and r = 0.583) but not with that of norantipyrine. The microsomal cholesterol content was increased by 16% and 90% in CCl4 and bile duct-ligated cirrhotic rats (P < 0.001), respectively. Membrane fluidity, expressed as the ratio of phospholipids to cholesterol, correlated with the in vivo clearance for production of norantipyrine (r = 0.841) but not of 3-OH- or 4-OH-antipyrine, while clearance in vitro was not related to altered lipid composition. Our results demonstrate that the cytochrome P450 isoenzymes responsible for the different pathways of antipyrine metabolism are affected to different extents by cirrhosis. Alterations in intrinsic clearance explain only part of the loss of hepatocellular function. Altered lipid composition contributes to this loss of function but other factors, among them loss of hepatocytes and changes in microcirculation, could be more important determinants of the decrease in xenobiotic metabolism in cirrhosis.
安替比林代谢至少依赖于细胞色素P450的三种同工酶，它们形成主要代谢产物3 - 羟基 - 、4 - 羟基 - 和去甲安替比林。我们研究了在大鼠肝硬化的两种模型中，安替比林清除率和代谢产物形成受损的程度，这两种模型分别是慢性暴露于苯巴比妥/CCl4诱导的小结节性肝硬化和胆管结扎诱导的胆汁性肝硬化。在CCl4和胆管结扎诱导的肝硬化中，唾液安替比林清除率下降程度相似（-35%）。两种模型中3 - 羟基安替比林生成的清除率均下降，而4 - 羟化作用得以维持。体内3 - 羟基安替比林和4 - 羟基安替比林的代谢清除率与其体外清除率相关（r = 0.658和r = 0.583），但与去甲安替比林的清除率无关。在CCl4和胆管结扎的肝硬化大鼠中，微粒体胆固醇含量分别增加了16%和90%（P < 0.001）。以磷脂与胆固醇的比值表示的膜流动性与去甲安替比林生成的体内清除率相关（r = 0.841），但与3 - 羟基 - 或4 - 羟基安替比林的清除率无关，而体外清除率与脂质组成改变无关。我们的结果表明，负责安替比林不同代谢途径的细胞色素P450同工酶受肝硬化影响的程度不同。内在清除率的改变仅部分解释了肝细胞功能的丧失。脂质组成的改变促成了这种功能丧失，但其他因素，包括肝细胞丢失和微循环变化，可能是肝硬化中外源性物质代谢减少的更重要决定因素。
