目的 研究異鼠李素對肝臟6種CYPs的體外抑制作用，以及對大鼠原代肝細(xì)胞的毒性作用。方法 采用人肝微粒體（HLMs）體外溫孵法研究異鼠李素對6種細(xì)胞色素P450酶（CYPs）——CYP2C19、CYP2D6、CYP3A4、CYP2E1、CYP1A2和CYP2C9的體外抑制作用；使用HPLC-MS/MS法檢測異鼠李素和HLMs共同孵育后的代謝產(chǎn)物；利用體外培養(yǎng)的低CYPs活性的大鼠原代肝細(xì)胞，考察不同劑量異鼠李素對細(xì)胞培養(yǎng)液中乳酸脫氫酶（LDH）、丙氨酸氨基轉(zhuǎn)移酶（ALT）、天門冬氨酸氨基轉(zhuǎn)移酶（AST）的影響。結(jié)果 50 μmol/L的異鼠李素對CYP2E1和CYP1A2有一定的抑制作用，抑制率分別為59.48%和39.91%；異鼠李素和HLMs共同孵育后，產(chǎn)生去甲基化代謝產(chǎn)物3,3',4',5,7-五羥基黃酮，轉(zhuǎn)化為極性和水溶性較高的代謝物；30、100、300 μmol/L的異鼠李素會使大鼠原代肝細(xì)胞培養(yǎng)液中的ALT和LDH顯著上升（P＜0.01），100、300 μmol/L異鼠李素使AST顯著上升（P＜0.05、0.01），呈濃度相關(guān)性。結(jié)論 異鼠李素在體外主要經(jīng)HLMs代謝，同時對CYP2E1和CYP1A2有一定的抑制作用，可能會使CYP2E1和CYP1A2的底物藥物在體內(nèi)的濃度產(chǎn)生變化，導(dǎo)致一系列藥物的相互作用；大量使用異鼠李素可能會造成一定程度的肝細(xì)胞損傷，且呈現(xiàn)濃度相關(guān)性。臨床應(yīng)用應(yīng)合理設(shè)置劑量，并注意潛在的藥物之間的相互作用。

Objective To study the inhibitory effects of isorhamnetin on six kinds of CYPs of liver in vitro, and the toxic effect on rat hepatocytes Methods This report uses warm incubation of human liver microsomes in vitro to investigate the inhibition of isorhamnetin on 6 kinds of CYPs (CYP2C19, CYP2D6, CYP3A4, CYP2E1, CYP1A2 and CYP2C9), and using HPLC-MS/MS to detect product of metabolism as well as analysing of the pathways of metabolic. At the same time, using rat primary hepatocytes which has low CYPs activity in vitro to explore whether the use of isorhamnetin will cause effects on the ALT, AST and LDH of hepatocytes. Results Isorhamnetin has inhibition effects on CYP2E1 and CYP1A2, the inhibition rate were 59.48% and 39.91%, respectively. Methylated metabolite is produced after incubating of isorhamnetin and HLMs. The isorhmnetin becomes high polarity and water solubility metabolite 3, 3', 4', 5, 7-hydroxyflavone. Isorhamnetin of 30, 100 and 300 μmol/L cause a significant rise of ALT and LDH in primary cultured rat hepatocytes cultured (P< 0.01). isorhamnetin of 100 μmol/L cause a rise of AST in primary cultured rat hepatocytes cultured (P< 0.05) and 300 μmol/L cause a significant rise (P< 0.01). It was a dose-dependent manner. Conclusion Isorhamnetin in vitro mainly metabolized by HLMs, and at the same time have a certain inhibitory effect on CYP2E1 and CYP1A2, which may cause the drugs which are metabolized by CYP2E1 and CYP1A2 in vivo accumulation that lead to a series of drug interactions. The results also indicate that heavy use of isorhamnetin cause some adverse effects on hepatocytes, and it was a dose-dependent manner. Individuals need to pay attention to the dose of isorhamnetin and the potential drug interactions.

國家自然科學(xué)基金面上項目（81373890）；教育部“創(chuàng)新團隊發(fā)展計劃”（IRT_14R41）