Abstract

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, FeSO₄ loading (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.

摘要

对乙酰氨基酚（APAP）过量是药物引起的急性肝功能衰竭的主要原因。在这种情况下，游离铁从溶酶体中释放出来并被转运到线粒体，在那里它在 APAP 诱导的肝损伤中起关键作用。我们之前报道过抗坏血酸 (Asc) 显着减轻了醛还原酶 (Akr1a) 基因敲除 (KO) 小鼠中 APAP 诱导的肝损伤，这些小鼠产生约 10% 的 Asc 作为野生型 (WT) 小鼠。然而，Asc 的保护机制与铁的状态有关的问题仍然不明确。为了进一步了解这个问题，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。虽然没有补充 AsA 的 KO 小鼠比 WT 小鼠对 APAP 毒性更敏感，但 FeSO ₄WT小鼠的负荷（25 mg / kg）加重了肝损伤，其程度与KO小鼠相似。补充 Asc（饮用水中 1.5 毫克/毫升）改善了 KO 小鼠，而与铁状态无关，但没有改变铁介导的 WT 小鼠致死率的增加。无论铁状态如何，所有小鼠组的肝脏半胱氨酸和谷胱甘肽水平在 3 小时时下降到相似的程度，并且在 APAP 治疗后 18 小时肝损伤明显时基本恢复。无论铁状态如何，Asc 都显着减轻了 KO 小鼠的 APAP 毒性，但对 WT 小鼠中铁和 APAP 的协同作用没有影响，这表明负载铁的恶化作用机制与 APAP 毒性的机制不同。