Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Toxicol Sci. 2012 Oct;129(2):456-68. doi: 10.1093/toxsci/kfs211. Epub 2012 Jul 12.
Rifaximin, a nonsystemic antibiotic that exhibits low gastrointestinal absorption, is a potent agonist of human pregnane X receptor (PXR), which contributes to its therapeutic efficacy in inflammatory bowel disease. To investigate the effects of long-term administration of rifaximin on the liver, PXR-humanized mice were administered rifaximin for 6 months; wild-type and Pxr-null mice were treated in parallel as controls. Histological analysis revealed time-dependent intense hepatocellular fatty degeneration and increased hepatic triglycerides in PXR-humanized mice and not in wild-type and Pxr-null mice. After long-term treatment, PXR target genes were induced in small intestine and liver, with significant up-regulation in the expression of hepatic genes related to triglyceride synthesis and lipid accumulation. However, no significant hepatic accumulation of rifaximin was found, even after 6 months of treatment, in PXR-humanized mice. Genes in the small intestine that are involved in the uptake of fatty acids and triglycerides were induced along with increased triglyceride accumulation in intestinal epithelial cells of PXR-humanized mice; this was not observed in wild-type and Pxr-null mice. These findings suggest that long-term administration of rifaximin could lead to PXR-dependent hepatocellular fatty degeneration as a result of activation of genes involved in lipid uptake, thus indicating a potential adverse effect of rifaximin on liver function after long-term exposure.
利福昔明是一种非系统性抗生素，其在胃肠道中的吸收较低，它是人类孕烷 X 受体 (PXR) 的有效激动剂，这有助于其在炎症性肠病中的治疗效果。为了研究利福昔明长期给药对肝脏的影响，将 PXR 人源化小鼠给予利福昔明治疗 6 个月；同时作为对照，给予野生型和 Pxr 基因敲除小鼠进行平行治疗。组织学分析显示，PXR 人源化小鼠存在时间依赖性的强烈肝细胞脂肪变性和肝内三酰甘油增加，而野生型和 Pxr 基因敲除小鼠则没有这种情况。长期治疗后，小肠和肝脏中的 PXR 靶基因被诱导，与三酰甘油合成和脂质积累相关的肝基因表达显著上调。然而，即使在 PXR 人源化小鼠中治疗 6 个月后，也未发现利福昔明在肝脏中有明显蓄积。与 PXR 人源化小鼠的小肠中脂肪酸和三酰甘油摄取相关的基因被诱导，同时肠上皮细胞中的三酰甘油积累增加；而在野生型和 Pxr 基因敲除小鼠中则未观察到这种情况。这些发现表明，利福昔明的长期给药可能导致 PXR 依赖性的肝细胞脂肪变性，这是由于参与脂质摄取的基因被激活所致，这表明利福昔明在长期暴露后可能对肝功能产生潜在的不良影响。
