目的 研究對(duì)乙酰氨基酚（APAP）對(duì)斑馬魚(yú)幼魚(yú)的肝臟毒性，并驗(yàn)證斑馬魚(yú)模型用于藥物肝毒性快速評(píng)價(jià)的實(shí)用性。方法 以發(fā)育72 hpf的肝臟熒光轉(zhuǎn)基因斑馬魚(yú)幼魚(yú)（L-FABP：EGFP）為實(shí)驗(yàn)對(duì)象，不同濃度的APAP分別處理斑馬魚(yú)幼魚(yú)，于處理后24、48、72 h，體視顯微鏡下觀察幼魚(yú)的死亡率、肝臟形態(tài)學(xué)變化和卵黃囊吸收情況，熒光顯微鏡下觀察APAP對(duì)幼魚(yú)肝臟熒光的影響。結(jié)果 APAP對(duì)斑馬魚(yú)幼魚(yú)存活率的影響呈劑量和時(shí)間相關(guān)性。APAP處理后的幼魚(yú)肝臟形態(tài)出現(xiàn)異常、肝臟顏色變暗，卵黃囊腫。與空白對(duì)照組相比，APAP處理后的幼魚(yú)肝組織L-FABP熒光表達(dá)明顯下降，肝臟明顯萎縮退化。結(jié)論 APAP對(duì)斑馬魚(yú)幼魚(yú)具有肝臟毒性。肝臟熒光轉(zhuǎn)基因斑馬魚(yú)模型快速評(píng)價(jià)藥物的肝臟毒性具有較好的應(yīng)用前景。

Objective To determine the hepatotoxicity of acetaminophen (APAP) in larval zebrafish and to validate the practicability of zebrafish model for rapid assessment of drug hepatotoxicity. Methods 72 hpf liver fluorescence transgenic zebrafish larvae (L-FABP: EGFP) were administered with APAP at four dosage series for 24, 48, and 72 h, respectively. Larval zebrafish mortality, liver morphology, yolk sac retention, and changes in liver fluorescence were evaluated to study the hepatotoxic effects of APAP. Results The effect of APAP on mortality of larval zebrafish was dose- and time-dependent. Larval zebrafish treated with APAP exhibited liver malformation, discoloration, hepatatrophia, and vitelline cyst. Compared with the control group, the liver fluorescence intensity significantly decreased in the larval zebrafish treated with APAP. Conclusion APAP could induce the liver damage in larval zebrafish. And using zebrafish as a reliable mammal model for screening hepatotoxic agents has good application prospects.

國(guó)家自然科學(xué)基金（81202584），山東省科學(xué)院青年科學(xué)基金項(xiàng)目（魯科院字2012第100號(hào)）資助