Bendele A M, Hoover D M, van Lier R B, Foxworthy P S, Eacho P I
Toxicology Division, Lilly Research Laboratories, Eli Lilly and Company, Greenfield, Indiana 46140.
Fundam Appl Toxicol. 1990 Nov;15(4):676-82. doi: 10.1016/0272-0590(90)90184-l.
A 2-year toxicity/oncogenicity study was done to evaluate the potential effects of the leukotriene antagonist LY171883 in B6C3F1 mice. Dietary concentrations of LY171883 during the initial 7 months of the study were 0.0, 0.005, 0.015, or 0.05% but were increased to 0.0, 0.0075, 0.0225, or 0.075% during Months 7 through 24. The estimated average daily compound intake was 0.0, 7.3, 22.5, or 80.5 mg/kg for males and 0.0, 9.2, 27.5, or 95.9 mg/kg for females. Survival was not adversely affected by treatment, however, body weight of males and females in the high dose group was significantly lower than that of controls. The chronic toxicity was localized primarily to the liver. Liver weights were increased in males in the high dose group and in females in the mid and high dose groups. Microsomal p-nitroanisole-O-demethylase activity was increased in mid and high dose females. Hepatic peroxisomal beta-oxidation was increased approximately twofold in both sexes in the high dose group only. Centrilobular eosinophilic granular change of hepatocytes was a common histopathologic finding in male and female mice in the high dose group, with the incidence and severity being greater in females. An increased incidence of hepatocellular carcinomas was observed in female mice in the mid and high dose groups. The number of male mice in the high dose group with hepatocellular carcinomas was higher than that of controls but the change was not statistically significant. Hepatocellular adenomas were increased in females in the high dose group but not in males. All groups of treated females had increased nodular hepatocellular hyperplasia.(ABSTRACT TRUNCATED AT 250 WORDS)
进行了一项为期两年的毒性/致癌性研究，以评估白三烯拮抗剂LY171883对B6C3F1小鼠的潜在影响。在研究的最初7个月中，LY171883的饮食浓度分别为0.0%、0.005%、0.015%或0.05%，但在第7至24个月期间增加到0.0%、0.0075%、0.0225%或0.075%。雄性小鼠的估计平均每日化合物摄入量分别为0.0、7.3、22.5或80.5毫克/千克，雌性小鼠为0.0、9.2、27.5或95.9毫克/千克。治疗对存活率没有不利影响，然而，高剂量组雄性和雌性小鼠的体重显著低于对照组。慢性毒性主要局限于肝脏。高剂量组雄性和中、高剂量组雌性的肝脏重量增加。中、高剂量雌性小鼠的微粒体对硝基苯甲醚-O-脱甲基酶活性增加。仅在高剂量组中，两性的肝过氧化物酶体β-氧化增加了约两倍。高剂量组雄性和雌性小鼠肝细胞中央小叶嗜酸性颗粒变化是常见的组织病理学发现，雌性的发生率和严重程度更高。在中、高剂量组雌性小鼠中观察到肝细胞癌的发生率增加。高剂量组患有肝细胞癌的雄性小鼠数量高于对照组，但变化无统计学意义。高剂量组雌性小鼠的肝细胞腺瘤增加，雄性小鼠则未增加。所有治疗组的雌性小鼠均出现结节性肝细胞增生增加。（摘要截断于250字）
