School of Life Sciences, Lanzhou University, Lanzhou, China.
Gansu Provincial Clinical Research Center for Laboratory Medicine, Gansu Provincial Hospital, Lanzhou, China.
J Appl Toxicol. 2024 Jun;44(6):863-873. doi: 10.1002/jat.4587. Epub 2024 Feb 4.
Although the medicinal properties of colchicine (COL) have been widely known for centuries, its toxicity has been the subject of controversy. The narrow therapeutic window causes COL to induce gastrointestinal adverse effects even when taken at recommended doses, mainly manifested as nausea, vomiting, and diarrhea. However, the mechanism of COL-induced gastrointestinal toxic reactions remains obscure. In the present study, the mice were dosed with COL (2.5 mg/kg b.w./day) for a week to explore the effect of COL on bile acid metabolism and the mechanism of COL-induced diarrhea. The results showed that COL treatment affected liver biochemistry in mice, resulting in a significant down-regulation of the mRNA expression levels of bile acid biosynthesis regulators Cyp7a1, Cyp8b1, Cyp7b1, and Cyp27a1 in liver tissues. The mRNA expression levels of bile acid transporters Ntcp, Oatp1, Mrp2, Ibabp, Mrp3, Osta, and Ostb in liver and ileum tissues were also significantly down-regulated. In addition, COL treatment significantly inhibited the mRNA expression levels of Fxr and its downstream target genes Shp, Lrh1, and Fgf15 in liver and ileum tissues, affecting the feedback regulation of bile acid biosynthesis. More importantly, the inhibition of COL on bile acid transporters in ileal and hepatic tissues affected bile acid recycling in the ileum as well as their reuptake in the liver, leading to a significantly increased accumulation of bile acids in the colon, which may be an important cause of diarrhea. In conclusion, our study revealed that COL treatment affected bile acid biosynthesis and enterohepatic circulation, thereby disrupting bile acid metabolic homeostasis in mice.
尽管秋水仙碱 (COL) 的药用特性已被广泛知晓数百年，但它的毒性一直存在争议。由于治疗窗狭窄，即使按照推荐剂量服用，COL 也会引起胃肠道不良反应，主要表现为恶心、呕吐和腹泻。然而，COL 引起胃肠道毒性反应的机制仍不清楚。在本研究中，我们用 COL（2.5mg/kg b.w./天）给小鼠灌胃一周，以探讨 COL 对胆汁酸代谢的影响及其引起腹泻的机制。结果表明，COL 处理影响了小鼠的肝功能，导致肝脏组织中胆汁酸生物合成调节剂 Cyp7a1、Cyp8b1、Cyp7b1 和 Cyp27a1 的 mRNA 表达水平显著下调。肝脏和回肠组织中胆汁酸转运体 Ntcp、Oatp1、Mrp2、Ibabp、Mrp3、Osta 和 Ostb 的 mRNA 表达水平也明显下调。此外，COL 处理显著抑制了肝脏和回肠组织中 Fxr 及其下游靶基因 Shp、Lrh1 和 Fgf15 的 mRNA 表达水平，影响了胆汁酸生物合成的反馈调节。更重要的是，COL 对回肠和肝脏组织中胆汁酸转运体的抑制作用影响了回肠中的胆汁酸循环以及在肝脏中的再摄取，导致结肠中胆汁酸的积累显著增加，这可能是腹泻的一个重要原因。综上所述，我们的研究表明，COL 处理影响了胆汁酸的生物合成和肠肝循环，从而破坏了小鼠的胆汁酸代谢平衡。
