肝细胞色素P450酶表达低下致何首乌特异质肝毒性机制研究

近年来何首乌相关临床肝损害发生较多，虽大多可逆，但也有转变成慢性肝炎甚至恶化发展的病例。目前何首乌致临床肝损害发生的原因仍不清楚。临床上部分何首乌相关肝损害有再激发和家族性发病特点，具药物特异质肝毒性特征。药物特异质肝毒性与肝细胞色素P450酶（CYP）的遗传多态性关系密切。我们前期研究发现，何首乌提取物可显著抑制大鼠肝CYP1A2、CYP2E1和CYP2C9的活性；用特异性抑制剂使大鼠肝P450酶表达低下，给予何首乌提取物，可致大鼠血清转氨酶显著升高。本项目在进一步阐明何首乌对大鼠肝P450酶表达影响的基础上，利用多种模型，如分别或联合应用肝P450酶的抑制剂抑制一种或多种P450酶的表达、利用RNA干扰基因表达的肝细胞，或基因敲除大鼠，研究何首乌提取物对肝P450酶表达低下或缺失的肝或肝细胞的损害及其机制；结合何首乌主要成分的肝P450酶生物转化特点，阐明何首乌肝损害发生的物质基础。

The reported cases of liver injury related to Polygonum multiflorum are increasing in recent years. Although most cases of the Polygonum multiflorum related liver damage are reversible, some cases do develop into chronic hepatitis and even lead to death. To this point, the cause of the liver injury related to Polygonum multiflorum remains unclear. Analysis of the clinical records revealed that some patients experienced recurred liver damage after Polygonum multiflorum readministration, and some patients had onset of liver damage with familial characteristics, which can be categorized as drug idiosyncratic hepatotoxicity. Drug idiosyncratic hepatotoxicity is often associated with genetic polymorphism of drug metabolizing enzymes, especially cytochrome P450 (CYP) in hepatic cells. Our recent data showed that water extract of Polygonum multiflorum significantly inhibited the activities of rat hepatic cytochrome P450 isoforms, CYP1A2, CYP2E1, and CYP2C9. In addition, water extract of Polygonum multiflorum caused a significant increase in serum transaminase after rats were pretreated with specific cytochrome P450 inhibitor. Using specific inhibitor for CYP1A2, CYP2E1, or CYP2C9 alone or in combination, RNA interference in hepatic cells, or gene knock-out transgenic rat to reduce or abolish cytochrome P450 expression, this project will clarify the effect of Polygonum multiflorum on the expression of hepatic cytochrome P450, and investigate the mechanism of how water extract of Polygonum multiflorum induces liver or liver cell damage. Moreover, the biotransformation features of chemical component in Polygonum multiflorum and the involvement of the specific P450 enzyme in the component biotransformation will be studied to elucidate the chemical basis of Polygonum multiflorum related liver injury.