Pill J, Völkl A, Hartig F, Fahimi H D
Medical Research Department, Boehringer Mannheim, FRG.
Arch Toxicol. 1992;66(5):327-33. doi: 10.1007/BF01973627.
The effects of bezafibrate administered at 10 and 50 mg/kg/day for 7 days to male Sprague-Dawley (SD) and Lewis rats were investigated in order to determine the interrelation between the changes in serum and hepatic lipid contents and activities of selected peroxisomal, microsomal and mitochondrial enzymes in the two rat strains. In both strains, bezafibrate effectively reduced serum and hepatic lipids, increased the liver weight, induced a proliferation of peroxisomes, and selectively elevated the activities of carnitine acetyltransferase and of the enzymes of the peroxisomal beta-oxidation system. Moreover, immunoblotting revealed that the drug specifically enhanced the concentration of only those peroxisomal enzymes involved in fatty acid beta-oxidation. The data obtained demonstrate that although the responses initiated by bezafibrate are qualitatively similar in both strains, they differ in their magnitude in a dose-dependent manner, with the Lewis strain exhibiting a more pronounced response than the SD rats. These results show that dose-dependent strain differences as well as the generally known species differences should be taken into account in pharmacological and toxicological evaluations of fibrates in rodents. Furthermore, generalization and extrapolation from rodent studies should be treated with great caution.
为了确定血清和肝脏脂质含量变化与所选过氧化物酶体、微粒体和线粒体酶活性之间的相互关系，研究了以10和50mg/kg/天的剂量给雄性斯普拉格-道利（SD）大鼠和刘易斯大鼠连续给药7天的苯扎贝特的作用。在这两种品系中，苯扎贝特均能有效降低血清和肝脏脂质，增加肝脏重量，诱导过氧化物酶体增殖，并选择性提高肉碱乙酰转移酶和过氧化物酶体β-氧化系统酶的活性。此外，免疫印迹显示该药物仅特异性增强参与脂肪酸β-氧化的那些过氧化物酶体酶的浓度。所获得的数据表明，虽然苯扎贝特引发的反应在两种品系中性质相似，但它们在剂量依赖性方面存在程度差异，刘易斯品系的反应比SD大鼠更为明显。这些结果表明，在对啮齿动物进行贝特类药物的药理学和毒理学评估时，应考虑剂量依赖性品系差异以及普遍已知的物种差异。此外，从啮齿动物研究进行的归纳和推断应极为谨慎。
