Price S C, Hinton R H, Mitchell F E, Hall D E, Grasso P, Blane G F, Bridges J W
Toxicology. 1986 Oct;41(2):169-91. doi: 10.1016/0300-483x(86)90198-8.
Groups of male Wistar albino rats were administered diets containing sufficient fenofibrate to ensure intakes of either 200, 60 or 13 mg/kg/day or sufficient clofibrate to ensure an intake of 400 mg/kg/day. Four rats from each experimental group and 6 control rats were killed, 3, 7, 14 and 28 days, 8, 12 and 20 weeks and 6, 9, 12 and 18 months after commencement of treatment. At all time points livers were subjected to histological, electron microscopic and biochemical examination, the other major abdominal organs were removed for histological examination. A more extensive necropsy was carried out on rats killed after 12 and 18 months. The major alterations were observed in the liver, although there were also morphological changes in the thyroid, pancreas and kidney after prolonged treatment. The hepatic changes followed a distinct time course. Within 24 h of offering diets containing the compounds to the rats there was accumulation of small droplets of lipid, induction of peroxisomal enzymes and of the specific cytochrome P-450 catalysing omega-hydroxylation of fatty acids and an increase in the number of mitotic figures. More slowly developing changes were loss from the centrilobular zone of fat, glycogen and of glucose 6-phosphatase activity. Here maximal changes were observed after 14 days of treatment. A still more slowly developing change was accumulation of enlarged lipid-loaded lysosomes, which was maximal at 26 weeks, accompanied by the development of lipofuscin bodies. Finally, in animals treated for 12 months or more there was evidence for increasing cell turnover as indicated by an increased number of mitotic figures, more dark cells and induction of serum alanine transaminase. The last 2 groups of changes were not observed in rats treated with 13 mg/kg/day of fenofibrate. In general the degree of change in rats treated with 400 mg/kg/day of clofibrate was similar to those found in rats treated with 60 mg/kg/day of fenofibrate.
将雄性Wistar白化大鼠分成几组，分别给予含有足够非诺贝特的饮食，以确保摄入量分别为200、60或13毫克/千克/天，或者给予含有足够氯贝丁酯的饮食，以确保摄入量为400毫克/千克/天。在治疗开始后的3天、7天、14天和28天、8周、12周和20周以及6个月、9个月、12个月和18个月，处死每个实验组的4只大鼠和6只对照大鼠。在所有时间点，对肝脏进行组织学、电子显微镜和生化检查，取出其他主要腹部器官进行组织学检查。对在12个月和18个月后处死的大鼠进行了更广泛的尸检。虽然长期治疗后甲状腺、胰腺和肾脏也有形态学变化，但主要变化发生在肝脏。肝脏变化遵循明显的时间进程。在给大鼠提供含有这些化合物的饮食后的24小时内，出现了小脂滴的积累、过氧化物酶体酶以及催化脂肪酸ω-羟化的特定细胞色素P-450的诱导，并且有丝分裂图数量增加。发展较慢的变化是中央小叶区脂肪、糖原和葡萄糖6-磷酸酶活性的丧失。在这里，治疗14天后观察到最大变化。发展更慢的变化是扩大的脂负载溶酶体的积累，在26周时达到最大值，同时伴有脂褐质小体的形成。最后，在治疗12个月或更长时间的动物中，有证据表明细胞更新增加，表现为有丝分裂图数量增加、更多的暗细胞以及血清丙氨酸转氨酶的诱导。在用13毫克/千克/天的非诺贝特治疗的大鼠中未观察到最后两组变化。一般来说，用400毫克/千克/天的氯贝丁酯治疗的大鼠的变化程度与用60毫克/千克/天的非诺贝特治疗的大鼠相似。
