Division of Pathology, National Institute of Health Sciences.
Biological Safety Research Center, National Institute of Health Sciences.
J Toxicol Sci. 2018;43(7):423-433. doi: 10.2131/jts.43.423.
Although obesity is increasing worldwide, experimental studies examining the possible association between obesity and susceptibility to chemical toxicity are limited. In the present study, we performed a 13-week toxicity study for acetaminophen (APAP), a well-known drug that exhibits hepatotoxicity as an adverse effect, using an obese rat model to investigate the differences in susceptibility between obese and normal individuals. Male F344 and obese Zucker (lean and fatty) rats were administered 0, 80, 253, 800, 2,530, or 8,000 ppm APAP in the diet for 13 weeks. No significant toxicity related to APAP treatment was observed in terms of clinical signs and hematology in all three strains. Body weight gain in F344 and lean rats was significantly decreased by 8,000 ppm APAP treatment. Significant increases in serum total cholesterol level and relative liver weights were detected in F344 rats in the highest dose group. On histopathological assessment, centrilobular hepatocellular hypertrophy was observed in the 8,000 ppm groups of F344 and lean rats, whereas no histopathological changes were induced by APAP in fatty rats. The no-observed-adverse-effect levels (NOAELs) of APAP were evaluated to be 2,530 ppm in F344 and lean rats (142.1 and 152.8 mg/kg bw/day, respectively) and more than 8,000 ppm in fatty rats (> 539.9 mg/kg bw/day). These results suggested that obese Zucker rats may be less susceptible to APAP-dependent toxicity in the liver than their lean counterparts.
尽管肥胖在全球范围内呈上升趋势，但研究肥胖与化学毒性易感性之间可能存在关联的实验研究却很有限。在本研究中，我们使用肥胖大鼠模型进行了为期 13 周的对乙酰氨基酚（APAP）毒性研究，以研究肥胖个体与正常个体之间易感性的差异，APAP 是一种已知具有肝毒性的药物，作为一种不良反应。雄性 F344 和肥胖 Zucker（瘦型和肥型）大鼠接受 0、80、253、800、2530 或 8000 ppm APAP 饲料喂养 13 周。在所有三种品系中，均未观察到与 APAP 治疗相关的临床症状和血液学毒性。F344 和瘦型大鼠的体重增加因 8000 ppm APAP 治疗而显著降低。在最高剂量组的 F344 大鼠中，血清总胆固醇水平和相对肝重显著增加。在组织病理学评估中，F344 和瘦型大鼠的 8000 ppm 组观察到中央小叶肝细胞肥大，而肥胖型大鼠的 APAP 未引起组织病理学变化。APAP 的无观察到不良效应水平（NOAEL）评估为 F344 和瘦型大鼠的 2530 ppm（分别为 142.1 和 152.8 mg/kg bw/day），肥胖型大鼠的 8000 ppm 以上（>539.9 mg/kg bw/day）。这些结果表明，肥胖 Zucker 大鼠对 APAP 诱导的肝毒性的易感性可能低于其瘦型大鼠。
