Effects of isorhamnetin on human liver microsomes CYPs and rat primary hepatocytes / 药物评价研究

ABSTRACT

Objective To study the inhibitory effects ofisorhamnetin 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).isorharnnetin 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 ofisorhamnetin and the potential drug interactions.