目的 通過連續(xù)28 d ig給予昆明小鼠大黃素，進(jìn)而對(duì)其全身毒性和潛在的肝、腎毒性進(jìn)行評(píng)價(jià)。方法 40只雄性昆明小鼠隨機(jī)分成溶媒對(duì)照組（0.5% CMC-Na）和大黃素低、中、高劑量（100、300、600 mg/kg）組，最初的最高給藥劑量為1 000 mg/kg，從給藥第6天起將給藥劑量調(diào)整為600 mg/kg，每組10只，連續(xù)給藥28 d后進(jìn)行解剖，給藥后第57天進(jìn)行恢復(fù)期解剖。給藥后觀察動(dòng)物的大體癥狀，并進(jìn)行體質(zhì)量和肝、脾、腎、腎上腺及腸系膜淋巴結(jié)質(zhì)量的測(cè)定、血清生化指標(biāo)檢測(cè)，以及大體和組織病理學(xué)檢查。結(jié)果 給藥結(jié)束，與溶劑對(duì)照組比較，大黃素高劑量組動(dòng)物的平均體質(zhì)量在試驗(yàn)的第3、7、10、14、17、21、28天顯著降低（P<0.05、0.01、0.001）；中、高劑量組動(dòng)物血清丙氨酸氨基轉(zhuǎn)移酶（ALT）水平升高，低、中劑量組動(dòng)物血清天冬氨酸氨基轉(zhuǎn)移酶（AST）水平升高，未見統(tǒng)計(jì)學(xué)的顯著性差異，低、中、高劑量組的其他血清生化指標(biāo)均未見明顯變化；低、中、高劑量組絕對(duì)臟器質(zhì)量及臟器指數(shù)均未見統(tǒng)計(jì)學(xué)的顯著性差異。試驗(yàn)期間高劑量組共有6只動(dòng)物死亡。死亡動(dòng)物大體剖檢可見脾體積減小，胸腺消失。死亡動(dòng)物肝鏡檢可見輕度肝細(xì)胞壞死、輕度肝細(xì)胞變性/壞死伴炎性細(xì)胞浸潤(rùn)，以及極輕度色素沉著；腎鏡檢可見輕度腎小管變性/壞死、輕度腎小管變性/再生，以及輕度色素沉著；脾鏡檢可見輕度淋巴細(xì)胞數(shù)目減少和輕度易染體巨噬細(xì)胞增多。各組計(jì)劃剖檢動(dòng)物大體檢查未見異常。高劑量組動(dòng)物肝鏡檢可見極輕度至輕度色素沉著；腎鏡檢可見極輕度至輕度色素沉著、極輕度至輕度腎小管變性/再生；膽囊鏡檢可見極輕度至輕度透明變性、輕度膽囊結(jié)石及輕度炎性細(xì)胞浸潤(rùn)（中性粒細(xì)胞為主）。結(jié)論 高劑量的大黃素可對(duì)動(dòng)物產(chǎn)生明顯的全身毒性作用，并可造成肝、腎、膽囊、脾損傷，大黃素的膽囊毒性為研究大黃素的肝、膽毒性機(jī)制提供新的思路和方向。

Objective To evaluate the systemic toxicity and potential hepatotoxicity and nephrotoxicity of emodin monomer in Kunming mice by ig administration for 28 days. Methods 40 male Kunming (KM) mice were randomly divided into vehicle control group (0.5% CMC-Na), low dose (100 mg/kg emodin monomer), medium does (300 mg/kg emodin monomer) and high dose (1000 mg/kg emodin monomer, which was adjusted to 600 mg/kg after administrating on day 6), with 10 animals per group. Clinical symptoms of animals were observed after administration, and body weight and organ weights (include liver, spleen, kidney, adrenal gland and mesenteric lymph node), serum biochemical indicators were measured and detected, as well as gross and histopathological examination after administration. Results At the end of dosing, the mean body weight in the high dose group was significantly reduced on day 3, 7, 10, 14, 17, 21, and 28 of the experiment with a high statistical significance. There was no statistically significant difference in serum ALT levels in the middle dose and high dose groups and also in serum AST levels in the low dose group and the middle dose group. No significant change was observed in other serum biochemical indicators in the low dose group, medium dose group and high dose group. There was no statistically significant difference in absolute organ weight or relative organ/ body weight ratio in the low dose group, the medium dose group and the high dose group.A total of 6 animals in the high dose group died during the experiment. The spleen was decreased in size and the thymus was disappeared in the dead animals. Microscopic examination of the dead animals showed mild hepatocyte necrosis and mild hepatocyte degeneration/necrosis with inflammatory cell infiltration, as well as mild pigmentation; mild tubular degeneration/necrosis and mild tubular degeneration/regeneration are seen in the kidneys, as well as mild pigmentation; mild decreased lymphocyte number and mild increased number of tingible body macrophages were observed in the spleen. No abnormalities were found in the planned necropsy of each group. Microscopic examination showed minimal to mild pigmentation in the liver, minimal to mild pigmentation and mild renal tubular degeneration/ regeneration, as well as minimal to mild hyalinosis, mild biliary calculus and mild inflammatory cell infiltration (mainly neutrophils) in the gallbladder in the high dose group. Conclusion High-dose emodin monomer could produce evident systemic toxicity, and cause damages in liver, kidney, gall bladder and spleen. The gallbladder toxicity of emodin provides a new idea and direction for studying the mechanism of hepatotoxicity and biliary toxicity of emodin.

國(guó)家自然科學(xué)基金資助項(xiàng)目（81503347）；國(guó)家十三五“重大新藥創(chuàng)制”專項(xiàng)課題（2018ZX09201017）