Protective role of heme oxygenase-1 induction in carbon tetrachloride-induced hepatotoxicity
Protective role of heme oxygenase-1 induction in carbon tetrachloride-induced hepatotoxicity
复制标题
DOI：
10.1016/s0006-2952(03)00444-1
复制
发表时间：
2003-09-15
影响因子：
5.8
通讯作者：
Morita, K
中科院分区：
文献类型：
--
作者：
Nakahira, K;Takahashi, T;Morita, K
四氯化碳（CCl4）的还原性代谢被认为引起脂质过氧化，从而导致肝损伤。血红素加氧酶-1 (HO-1) （EC 1.14.99.3）是血红素分解代谢的限速酶，已知可由氧化应激诱导并赋予抗氧化组织损伤的保护作用。在这项研究中，我们研究了HO-1在ccl4诱导的大鼠急性肝损伤模型中的作用。CCl4 （1 mL/kg，腹腔注射）对大鼠造成严重肝损伤，血清丙氨酸转氨酶（EC 2.6.1.2）活性和肝脏丙二醛（MDA）含量显著升高，肝细胞严重损伤，肝肿瘤坏死因子- α (tnf - α) mRNA表达和核因子- κ b (nf - κ b) DNA结合活性升高。在CCl4治疗后，肝细胞中HO-1的转录和蛋白水平均显著升高，特别是在中央静脉周围。HO-1的诱导部分是通过微粒体游离血红素浓度的快速增加介导的，可能来源于肝细胞色素P450。鱼鳍-中卟啉（Sn-MP）抑制HO活性，导致微粒体游离血红素浓度持续升高，加重了肝损伤，这可以从血清ALT活性持续升高、肝细胞广泛损伤、肝脏TNF-a mRNA表达更明显和NF-kappaB活化增强来判断。这些发现表明，HO-1的诱导是对CCl4治疗的适应性反应，它可能对肝细胞损伤后的恢复至关重要。我们的研究结果还表明，HO-1诱导可能在保护肝细胞免受游离血红素引起的氧化损伤方面发挥重要作用。(C) 2003 Elsevier Inc.版权所有。
Reductive metabolism of carbon tetrachloride (CCl4) is thought to cause lipid peroxidation which results in hepatic injury. Heme oxygenase-1 (HO-1) (EC 1.14.99.3), the rate-limiting enzyme in heme catabolism, is known to be induced by oxidative stress and to confer protection against oxidative tissue injuries. In this study, we examined the role of HO-1 induction in a rat model of CCl4-induced acute liver injury. CCl4 treatment (1 mL/kg, intraperitoneally) produced severe hepatic injury in rats as revealed by significant increases in serum alanine transaminase (ALT) (EC 2.6.1.2) activity and hepatic malondialdehyde (MDA) content, severe liver cell injury, and increases in hepatic tumor necrosis factor-alpha (TNF-alpha) mRNA expression and DNA binding activity of nuclear factor-kappaB (NF-kappaB). Following CCl4 treatment, hepatic HO-1 expression was markedly increased both at transcriptional and protein levels in hepatocytes, especially around the central vein. HO-1 induction was mediated in part through a rapid increase in microsomal free heme concentration presumably derived from hepatic cytochrome P450. Inhibition of HO activity by fin-mesoporphyrin (Sn-MP), which resulted in a sustained increase in microsomal free heme concentration, exacerbated liver injury, as judged by the sustained increase in serum ALT activity, extensive hepatocytes injuries, a more pronounced expression of hepatic TNF-a mRNA and an enhanced NF-kappaB activation. These findings indicate that induction of HO-1 is an adaptive response to CCl4 treatment, and it may be critical in the recovery of hepatocytes from injury. Our findings also suggest that HO-1 induction may play an important role in conferring protection on hepatocytes from oxidative damage caused by free heme. (C) 2003 Elsevier Inc. All rights reserved.