Immature mice are more susceptible than adult mice to acetaminophen-induced acute liver injury.
Immature mice are more susceptible than adult mice to acetaminophen-induced acute liver injury.
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未成熟小鼠比成年小鼠更容易受到对乙酰氨基酚引起的急性肝损伤
DOI：
10.1038/srep42736
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发表时间：
2017-02-16
影响因子：
4.6
通讯作者：
Xu DX
中科院分区：
文献类型：
--
作者：
Lu Y;Zhang C;Chen YH;Wang H;Zhang ZH;Chen X;Xu DX
对乙酰氨基酚（APAP）过量可引起急性肝损伤。本研究的目的是分析未成年和成年小鼠对APAP诱导的急性肝损伤易感性的差异。给断奶的未成熟和成年小鼠注射APAP（300 mg/kg）。正如预期的那样，未成熟的小鼠比成年小鼠更容易受到APAP诱导的急性肝损伤。APAP诱导的肝脏c-Jun N-末端激酶磷酸化在未成熟小鼠中比在成年小鼠中更强。APAP暴露的未成年和成年小鼠肝受体相互作用蛋白（RIP）1明显激活。有趣的是，APAP处理的未成熟小鼠的肝脏RIP 3激活比成年小鼠更明显。虽然未成熟小鼠和成年小鼠的肝脏GSH代谢酶没有差异，但未成熟小鼠比成年小鼠更容易受到APAP诱导的肝脏GSH耗竭。值得注意的是，未成熟小鼠的肝脏Cyp 2 e1和Cyp 3a 11 mRNA表达水平比成年小鼠高得多。相应地，未成熟小鼠表达较高水平的肝脏CYP 2 E1，这是将APAP代谢为反应性代谢物NAPQI的关键药物代谢酶。这些结果表明，未成年小鼠肝脏药物代谢酶水平高于成年小鼠可能有助于对APAP诱导的急性肝损伤的易感性差异。
Acetaminophen (APAP) overdose induces acute liver injury. The aim of the present study was to analyze the difference of susceptibility between immature and adult mice to APAP-induced acute liver injury. Weanling immature and adult mice were injected with APAP (300 mg/kg). As expected, immature mice were more susceptible than adult mice to APAP-induced acute liver injury. APAP-evoked hepatic c-Jun N-terminal kinase phosphorylation was stronger in immature mice than in adult mice. Hepatic receptor-interacting protein (RIP)1 was obviously activated at APAP-exposed immature and adult mice. Interestingly, hepatic RIP3 activation was more obvious in APAP-treated immature mice than adult mice. Although there was no difference on hepatic GSH metabolic enzymes between immature and adult mice, immature mice were more susceptible than adult mice to APAP-induced hepatic GSH depletion. Of interest, immature mice expressed a much higher level of hepatic Cyp2e1 and Cyp3a11 mRNAs than adult mice. Correspondingly, immature mice expressed a higher level of hepatic CYP2E1, the key drug metabolic enzyme that metabolized APAP into the reactive metabolite NAPQI. These results suggest that a higher level of hepatic drug metabolic enzymes in immature mice than adult mice might contribute to the difference of susceptibility to APAP-induced acute liver injury.