Susceptibility to acetaminophen (APAP) toxicity unexpectedly is decreased during acute viral hepatitis in mice.
Susceptibility to acetaminophen (APAP) toxicity unexpectedly is decreased during acute viral hepatitis in mice.
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DOI：
10.1016/j.bcp.2009.12.019
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发表时间：
2010-05-01
影响因子：
5.8
通讯作者：
Miller, Bonnie C.
中科院分区：
文献类型：
--
作者：
Getachew, Yonas;James, Laura;Lee, William M.;Thiele, Dwain L.;Miller, Bonnie C.
对乙酰氨基酚（APAP）的肝毒性是由于APAP的细胞色素P450代谢成毒性代谢物n-乙酰基苯醌亚胺（NAPQI）， NAPQI与半胱氨酸残基反应形成APAP加合物并引发细胞损伤。由于APAP通常用于病毒性疾病，因此人们担心APAP损伤可能会增加病毒性肝炎的损伤，因此医生建议不要在此类患者中使用APAP；这还没有经过实验研究。我们用复制缺陷腺病毒感染C57BL/6雄性小鼠，使其产生中重度急性病毒性肝炎，并观察到，在病毒诱导的肝损伤高峰期给药时，在对照小鼠中具有肝毒性或致死剂量的APAP既不会导致死亡，也不会增加血清ALT。此外，这些小鼠肝脏中形成的apap蛋白加合物浓度仅为对照组的10%。在感染过程的早期，在病毒诱导的ALT峰值升高之前，也观察到APAP对肝毒性的保护作用。肝谷胱甘肽限制了apap蛋白加合物的形成，但对照组和感染小鼠的谷胱甘肽水平相似。Cyp1a2 （E.C. 1.14.14.1）和Cyp2e1 （E.C. 1.14.13）。n7) mRNA表达在感染后第3天下降，肝脏Cyp2e1蛋白水平在第7天下降近90%，此时加合物的形成受到最大程度的抑制。在体外，病毒感染小鼠的肝细胞对apap诱导的损伤也有抗性，但对NAPQI敏感。在该模型中，急性病毒性肝炎并没有增强APAP诱导的肝损伤，而是导致肝脏中APAP代谢p450选择性下调，降低了APAP肝毒性的风险。
Acetaminophen (APAP) hepatotoxicity results from cytochrome P450 metabolism of APAP to the toxic metabolite, n-acetyl-benzoquinone imine (NAPQI), which reacts with cysteinyl residues to form APAP adducts and initiates cell injury. As APAP is commonly used during viral illnesses there has been concern that APAP injury may be additive to that of viral hepatitis, leading physicians to advise against its use in such patients; this has not been investigated experimentally. We infected C57BL/6 male mice with replication-deficient adenovirus to produce moderately severe acute viral hepatitis and observed that APAP doses that were hepatotoxic or lethal in control mice produced neither death nor additional increase in serum ALT when administered to infected mice at the peak of virus-induced liver injury. Moreover, the concentration of hepatic APAP-protein adducts formed in these mice was only 10% that in control mice. Protection from APAP hepatotoxicity also was observed earlier in the course of infection, prior to the peak virus-induced ALT rise. Hepatic glutathione limits APAP-protein adduct formation but glutathione levels were similar in control and infected mice. Cyp1a2 (E.C. 1.14.14.1) and Cyp2e1 (E.C. 1.14.13.n7) mRNA expression decreased by 3 days post-infection and hepatic Cyp2e1 protein levels were reduced almost 90% at 7 days, when adduct formation was maximally inhibited. In vitro, hepatocytes from virally infected mice also were resistant to APAP-induced injury but sensitive to NAPQI. Rather than potentiating APAP-induced liver injury, acute viral hepatitis in this model resulted in selective down-regulation of APAP metabolizing P450s in liver and decreased the risk of APAP hepatotoxicity.
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