Effects of lipopolysaccharide-stimulated inflammation and pyrazole-mediated hepatocellular injury on mouse hepatic Cyp2a5 expression
Effects of lipopolysaccharide-stimulated inflammation and pyrazole-mediated hepatocellular injury on mouse hepatic Cyp2a5 expression
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DOI：
10.1016/s0300-483x(02)00581-4
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发表时间：
2003-03-03
期刊：
影响因子：
4.5
通讯作者：
Kirby, GM
中科院分区：
文献类型：
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作者：
Gilmore, WJ;Hartmann, G;Kirby, GM
小鼠肝细胞色素P450 2a5（Cyp2a5）在肝毒性和肝炎过程中被诱导，但具体的调节机制尚未确定。我们比较了细菌内毒素脂多糖（LPS）引起的体内急性炎症和肝毒素吡唑引起的肝损伤对小鼠肝脏 Cyp2a5 表达的影响。吡唑处理导致 Cyp2a5 mRNA、蛋白质和催化活性水平分别显着增加 540%、273% 和 711%（P < 0.05）。在 LPS 处理的肝脏中，与对照组相比，Cyp2a5 的 mRNA (46%)、蛋白质 (35%) 和活性 (23%) 水平表达显着降低 (P < 0.05)。用重组鼠白细胞介素 1β 和白细胞介素 6 治疗小鼠对 Cyp2a5 mRNA 和蛋白质水平没有显着影响。通过血清丙氨酸氨基转移酶评估，吡唑组的肝损伤比 LPS 治疗组更大（分别为对照水平的 609% 和 354%）。由肝葡萄糖调节蛋白 78 (grp78) 水平决定的 ER 应激，吡唑组（对照组为 185%）比 LPS（对照组为 128%）更大。在吡唑处理的肝脏中，免疫反应性 grp78 蛋白的过度表达表明，ER 应激局限于中央周围肝细胞，其中 Cyp2a5 被诱导。这些细胞中糖原损失和膜损伤的证据表明存在氧化损伤。此外，维生素 E 减弱体内吡唑对 Cyp2a5 的诱导。这些结果表明，在小鼠肝炎和肝毒性模型中观察到的 Cyp2a5 诱导可能与中央周围肝细胞内质网的氧化损伤有关，而不是与促炎细胞因子的暴露有关。 (C) 2002 Elsevier Science Ireland Ltd. 保留所有权利。
Murine hepatic cytochrome P450 2a5 (Cyp2a5) is induced during hepatotoxicity and hepatitis, however, the specific regulatory mechanisms have not been determined. We compared the influence of acute inflammation elicited in vivo by bacterial endotoxin lipopolysaccharide (LPS) and liver injury caused by the hepatotoxin pyrazole on hepatic Cyp2a5 expression in mice. Pyrazole treatment resulted in statistically significant increases in levels of Cyp2a5 mRNA, protein and catalytic activity by 540, 273 and 711%, respectively (P < 0.05). In LPS-treated livers Cyp2a5 expression was significantly reduced compared to controls at the mRNA (46%) protein (35%), and activity (23%) levels (P < 0.05). Treatment of mice with recombinant murine interleukin-1 beta and interleukin-6 had no significant effect on Cyp2a5 mRNA and protein levels. Liver injury, as assessed by serum alanine aminotransferase, was greater with pyrazole, than with LPS treatment (609 vs 354% of control levels respectively). ER stress, determined by hepatic glucose regulated protein 78 (grp78) levels, was greater with pyrazole (185% of controls) than with LPS (128% of controls). In pyrazoletreated liver, overexpression of immunoreactive grp78 protein revealed that ER stress was localized to pericentral hepatocytes in which Cyp2a5 was induced. Evidence of glycogen loss and membrane damage in these cells was suggestive of oxidative damage. Moreover, vitamin E attenuated Cyp2a5 induction by pyrazole in vivo. These results suggest that induction of Cyp2a5 that has been observed in mouse models of hepatitis and hepatoxicity May be related to oxidative injury to the endoplasmic reticulum of pericentral hepatocytes rather than exposure to pro-inflammatory cytokines. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved.