Sabzevari O, Hatcher M, Kentish P, O'Sullivan M, Gibson G G
University of Surrey, School of Biological Sciences, Guildford, UK.
Toxicology. 1996 Jan 8;106(1-3):19-26. doi: 10.1016/0300-483x(95)03150-e.
Male Wistar rats were treated with a low (150 mumol/kg) and a high (750 mumol/kg) dose of either clotrimazole of bifonazole. Bifonazole, but not clotrimazole, exhibited the characteristics of a peroxisome proliferator including hepatomegaly (increase in liver:body weight ratio), up to a 4-fold induction of lauric acid omega-hydroxylase activity and an 8-fold induction of palmitoyl-CoA oxidation by rat liver peroxisomes. This induction of enzyme activities was paralleled by increased protein levels as determined by immunochemical analysis for both liver microsomal cytochrome P4504A1 and the peroxisomal trifunctional protein of the beta-oxidation spiral. In contrast, clotrimazole did not increase protein levels of either cytochrome P4504A or the trifunctional protein. Western blot analyses demonstrated that bifonazole also induced P4502B1/2B2, P4503A and P4501A1, but not P4502E1. Clotrimazole induced a similar spectrum of P450s as determined by Western blotting with the exception that this azole was a marginal P4501A1 inducer under the conditions studied. Taken collectively, our data provides evidence that bifonazole is one of the increasingly recognised, non-carboxylate containing xenobiotics that induce both peroxisome proliferation and the cytochrome P4504A sub-family in rat liver.
将雄性Wistar大鼠用低剂量（150微摩尔/千克）和高剂量（750微摩尔/千克）的克霉唑或联苯苄唑进行处理。联苯苄唑而非克霉唑表现出过氧化物酶体增殖剂的特征，包括肝肿大（肝脏与体重比增加）、大鼠肝脏过氧化物酶体对月桂酸ω-羟化酶活性的诱导高达4倍以及对棕榈酰辅酶A氧化的诱导高达8倍。通过对肝脏微粒体细胞色素P4504A1和β-氧化螺旋体的过氧化物酶体三功能蛋白进行免疫化学分析确定，酶活性的这种诱导与蛋白质水平的增加平行。相比之下，克霉唑并未增加细胞色素P4504A或三功能蛋白的蛋白质水平。蛋白质印迹分析表明，联苯苄唑还诱导了P4502B1/2B2、P4503A和P4501A1，但未诱导P4502E1。在研究条件下，克霉唑诱导的细胞色素P450谱与之相似，只是这种唑类药物是P4501A1的边缘诱导剂。总体而言，我们的数据提供了证据，表明联苯苄唑是越来越被认可且不含羧酸盐的外源性物质之一，它能诱导大鼠肝脏中的过氧化物酶体增殖和细胞色素P4504A亚家族。
