Iron loading exerts synergistic action via a different mechanistic pathway from that of acetaminophen-induced hepatic injury in mice
Iron loading exerts synergistic action via a different mechanistic pathway from that of acetaminophen-induced hepatic injury in mice
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铁负荷通过与对乙酰氨基酚诱导的小鼠肝损伤不同的机制途径发挥协同作用
DOI：
10.1080/10715762.2020.1819996
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发表时间：
2020
影响因子：
3.3
通讯作者：
Fujii Junichi
中科院分区：
文献类型：
--
作者：
Moon Gyul;Kobayashi Sho;Aung Naing Ye;Yamada Ken-ichi;Yamakawa Mitsunori;Fujii Junichi
对乙酰氨基酚（APAP）过量是药物性急性肝衰竭的主要原因。在这种情况下，游离铁从溶酶体释放并运输到线粒体，在apap诱导的肝损伤中起关键作用。我们之前报道了抗坏血酸（Asc）显著减轻apap诱导的醛还原酶（Akr1a）敲除（KO）小鼠的肝损伤，这些小鼠与野生型（WT）小鼠一样产生约10%的Asc。然而，Asc的保护机制与铁的地位之间的关系仍然不明确。为了进一步了解这一问题，我们研究了APAP （500 mg/kg）在铁负荷条件下对雌性KO小鼠的影响。未添加AsA的KO小鼠比WT小鼠对APAP毒性更敏感，而feso4 （25 mg/kg）对WT小鼠的肝损伤加重程度与KO小鼠相似。补充Asc（饮用水中1.5 mg/ml）改善了KO小鼠的铁状态，但没有改变铁介导的WT小鼠死亡率的增加。在所有小鼠组中，无论铁状态如何，肝脏半胱氨酸和谷胱甘肽水平在3 h时均有相似程度的下降，并在APAP治疗后18 h（肝损伤明显）时基本恢复。不论铁含量如何，Asc均显著减轻了KO小鼠的APAP毒性，但对WT小鼠中铁与APAP的协同作用没有影响，提示负载铁的恶化作用机制与APAP毒性作用不同。
Acetaminophen (APAP) overdose is a major cause of drug-induced acute liver failure. In such cases, free iron is released from lysosomes and is transported to mitochondria where it plays a pivotal role in APAP-induced liver injury. We previously reported that ascorbic acid (Asc) markedly mitigates APAP-induced hepatic damage in aldehyde reductase (Akr1a)-knockout (KO) mice that produce about 10% Asc as wild-type (WT) mice. However, the issue of the protective mechanism of Asc in association with the status of iron remains ambiguous. To gain additional insights into this issue, we examined effects of APAP (500 mg/kg) on female KO mice under conditions of iron loading. While the KO mice without AsA supplementation were more sensitive to APAP toxicity than the WT mice, FeSO4loading (25 mg/kg) to WT mice aggravated the hepatic injury, which was a similar extent to that of the KO mice. Supplementation of Asc (1.5 mg/ml in the drinking water) ameliorated KO mice irrespective of iron status but did not change the iron-mediated increase in the lethality in the WT mice. Hepatic cysteine and glutathione levels declined to similar extents in all mouse groups at 3 h irrespective of the iron status and largely recovered at 18 h after the APAP treatment when liver damage was evident. Asc prominently mitigated APAP toxicity in KO mice irrespective of the iron status but had no effect on the synergistic action of iron and APAP in the WT mice, suggesting that the mechanism for the deteriorating action of loaded iron is different from that of APAP toxicity.
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影响因子：
7.4
作者：
Traber, Maret G.;Stevens, Jan F.
通讯作者：
Stevens, Jan F.
DOI：
--
发表时间：
1988
期刊：
The Journal of pharmacology and experimental therapeutics
影响因子：
--
作者：
Z. Gregus;C. Madhu;C. Klaassen
通讯作者：
Z. Gregus;C. Madhu;C. Klaassen
对乙酰氨基酚诱导的肝毒性：对乙酰氨基酚诱导的铁死亡和线粒体损伤的不同机制
影响因子：
6.1
作者：
Naoya Yamada;Takanori Komada;N. Ohno;Masafumi Takahashi
通讯作者：
Masafumi Takahashi
抗坏血酸酯对用肝毒性剂量的对乙酰氨基酚治疗的小鼠肝脏谷胱甘肽水平的影响。
DOI：
10.1002/jbt.2570060203
发表时间：
1991
期刊：
Journal of biochemical toxicology
影响因子：
--
作者：
A. Mitra;A. Kulkarni;V. Ravikumar;D. R. Bourcier
通讯作者：
D. R. Bourcier
DOI：
--
发表时间：
1986-07
期刊：
The Journal of pharmacology and experimental therapeutics
影响因子：
--
作者：
George B. Corcoran;B. Wong
通讯作者：
George B. Corcoran;B. Wong