Endotoxin-mediated disturbance of hepatic cytochrome P450 function and development of endotoxin tolerance in the rat model of dextran sulfate sodium-induced experimental colitis
Endotoxin-mediated disturbance of hepatic cytochrome P450 function and development of endotoxin tolerance in the rat model of dextran sulfate sodium-induced experimental colitis
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DOI：
10.1124/dmd.32.4.437
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发表时间：
2004-04-01
影响因子：
3.9
通讯作者：
Horie, T
中科院分区：
文献类型：
--
作者：
Masubuchi, Y;Horie, T
慢性炎症性肠病患者存在肝胆异常。在葡聚糖硫酸钠 (DSS) 诱导的结肠炎大鼠中测定肝细胞色素 P450 (P450) 依赖性药物代谢酶活性和对肝毒素 D-半乳糖胺的敏感性，以评估炎症性肠病模型中肝功能是否受到影响。通过用3％DSS的饮用水处理大鼠7天来诱导结肠炎。从患有结肠炎的大鼠以及未治疗和脂多糖（LPS）治疗的大鼠中制备用于酶活性的肝微粒体和用于生物分析的血清。其他大鼠接受腹腔注射 D-半乳糖胺以评估其对毒素引起的肝损伤的易感性。用 DSS 治疗大鼠不仅会导致结肠炎，还会导致肝脏 P450 依赖性药物代谢酶活性降低。门静脉血内毒素升高，与肝损伤无关。 DSS 处理抑制 P450 酶的效力和异构体选择性与 LPS 处理的大鼠相似。抗生素、多粘菌素 B 或甲硝唑与 DSS 的共同给药可保护大鼠免受部分但不是全部 P450 酶活性的降低，表明细菌内毒素部分参与 P450 的降低。患有结肠炎的大鼠比未治疗的大鼠更不易受 D-半乳糖胺诱导的肝损伤和 TNF-α 产生的影响，这表明 DSS 结肠炎中出现了内毒素耐受性。总之，这些结果表明，DSS 结肠炎导致内毒素介导的肝 P450 酶下调，并防止 D-半乳糖胺诱导的肝损伤，这可能是由于内毒素耐受。
Hepatobiliary abnormalities have been described in patients with chronic inflammatory bowel diseases. Hepatic cytochrome P450 (P450)-dependent drug-metabolizing enzyme activities and susceptibility to a hepatotoxin, D-galactosamine, were determined in rats with dextran sulfate sodium (DSS)-induced colitis to assess whether liver function is affected in the model of inflammatory bowel disease. Colitis was induced by treatment of rats with 3% DSS in drinking water for 7 days. Liver microsomes for enzyme activities and serum for biological analysis were prepared from the rats with colitis, along with untreated and lipopolysaccharide (LPS)-treated rats. Other rats received intraperitoneal injection of D-galactosamine to assess their susceptibility to the toxin-induced liver injury. Treatment of rats with DSS resulted in not only colitis but also decreases in hepatic P450-dependent drug-metabolizing enzyme activities. Elevated endotoxin was found in portal blood, which was not associated with liver injury. The potency and the isoform selectivity in the suppression of the P450 enzymes by DSS treatment were similar to those of LPS-treated rats. Coadministration of antibiotics, polymyxin B or metronidazole, with DSS protected rats from decreases in some but not all P450 enzyme activities, indicating partial involvement of bacterial endotoxin in the P450 decreases. The rats with colitis were less susceptible than untreated rats to D-galactosamine-induced liver injury and TNF-alpha production, suggesting development of endotoxin tolerance in DSS-colitis. In conclusion, these results suggest that the DSS-colitis leads to endotoxin-mediated down-regulation of hepatic P450 enzymes and protection against D-galactosamine-induced liver injury, probably due to endotoxin tolerance.