Cytochrome P450 Dysregulations in Thioacetamide-Induced Liver Cirrhosis in Rats and the Counteracting Effects of Hepatoprotective Agents
Cytochrome P450 Dysregulations in Thioacetamide-Induced Liver Cirrhosis in Rats and the Counteracting Effects of Hepatoprotective Agents
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DOI：
10.1124/dmd.111.043539
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发表时间：
2012-04
影响因子：
3.9
通讯作者：
Yuan Xie;Guangji Wang;Hong Wang;Xilin Yao;Shan Jiang;An Kang;F. Zhou;Tong Xie;H. Hao
中科院分区：
文献类型：
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作者：
Yuan Xie;Guangji Wang;Hong Wang;Xilin Yao;Shan Jiang;An Kang;F. Zhou;Tong Xie;H. Hao
细胞色素P450(P450s)在肝损伤中的调节作用已被广泛研究。然而，目前对保肝药物可能的逆转作用知之甚少，了解其可能的逆转作用对指导肝损伤患者的临床剂量调整具有重要意义。本研究旨在探讨硫代乙酰胺(TAA)诱导的大鼠肝硬变模型中主要P450的异常调节模式，以及保肝药物五味子木脂素提取物(SLE)和二苯二甲酸二甲酯(DDB)的拮抗作用。TAA染毒6周后，大鼠肝脏出现明显的肝损伤，肝组织细胞色素P450 1A2、细胞色素P450 2 C6、细胞色素P2 E1和细胞色素P3A2的蛋白表达分别为正常对照组的18、71、30和21%。SLE和DDB均能显著逆转TAA所致的P450蛋白水平的降低，这可能是由于其保肝作用和直接诱导P450的作用已在健康大鼠中得到证实。然而，SLE和DDB处理对大多数P450酶活性的恢复不如对蛋白质表达水平的恢复明显。TAA对四种主要的P450同工酶均表现出NADPH、时间和浓度依赖的失活效应；DDB和GSH对这种失活效应的抑制作用很小。这些结果很好地解释了保肝药物在恢复TAA诱导的异常P450蛋白水平和酶活性方面的不成比例作用。
Dysregulations of cytochromes P450 (P450s) under liver injury have been extensively studied. However, little is known about the possible reversing effects of hepatoprotective agents, the understanding of which is of great importance in guiding clinical dosage adjustment for patients with liver injury. This study aims to investigate the dysregulation patterns of major P450s in thioacetamide (TAA)-induced liver cirrhosis in rats and the potential counteracting effects of hepatoprotective agents schisandra lignans extract (SLE) and dimethyl diphenyl bicarboxylate (DDB). TAA intoxications for 6 weeks induced apparent liver injury and dramatically reduced the hepatic protein expressions of CYP1A2, CYP2C6, CYP2E1, and CYP3A2 to 18, 71, 30, and 21% of that in the normal control, respectively. Both SLE and DDB treatments could significantly reverse the TAA-induced loss of P450 protein levels, which may be ascribed to their hepatoprotective effects and direct P450-inducing effects that have been confirmed in healthy rats. However, the recovery of enzyme activities of most P450s by SLE and DDB treatment was less evident than that for the protein expression levels. TAA exhibited NADPH-, time-, and concentration-dependent inactivating effects on all of the four major P450 isozymes; both DDB and GSH showed little effects on counteracting such an inactivation efficacy. These findings provided a good explanation on the disproportional effects of hepatoprotective agents in recovering the protein levels and enzyme activities of TAA-induced dysregulated P450s.