基于CYP450途径研究湖北海棠对利福平和异烟肼联用所致小鼠肝损伤的保护作用机制

Liver injury caused by anti-tuberculosis drugs accounts for a large proportion of drug-induced liver injury. Rifampicin (RFP)/isoniazid (INH) is a first-line anti-tuberculosis drug widely used in clinic. The combination of RFP and INH can synergize and reduce drug dependence, but can significantly increase hepatotoxicity. The increase of hepatotoxicity is due to the increase of hepatotoxic metabolites of INH induced by RFP to CYP450, which leads to oxidative damage of hepatocytes. The development of hepatoprotective agents with toxicity reducing and efficacy enhancing effects is necessary for the prevention and treatment of hepatotoxicity in the course of clinical tuberculosis treatment. Aiming at the clinical adverse drug reaction of hepatotoxicity caused by RFP/INH combination, based on the previous study of hepatoprotective effect of Malus hupehensis (MH), with CYP450 as the breakthrough point, the animal model of liver injury induced by RFP/INH was constructed, and the attenuation effect of MH was evaluated. From the perspective of CYP450 mRNA and protein expression, the regulation of MH on hepatic pharmacokinetic enzymes was discussed, and the possible mechanism of MH was elucidated.

抗结核药引起的肝损伤在药物性肝损伤中占据较大比例，利福平(RFP)/异烟肼(INH)是临床广泛使用的一线抗结核药，二者联用可协同增效且减少赖药性，但会明显增加肝毒性，其增加肝毒性的原因是RFP对CYP450的诱导引起INH肝毒性代谢产物的增加，导致肝细胞的氧化损伤。具有减毒增效作用肝保护剂的开发，对临床结核病治疗过程中肝毒性的防治成为必要。本课题针对RFP/INH联合用药引起肝毒性这一临床药物不良反应，在前期湖北海棠（MH）保肝作用研究基础上，以CYP450为切入点，构建RFP/INH肝损伤小鼠动物模型，评价MH的减毒作用，并从CYP450 mRNA和蛋白表达角度，探讨MH对肝药酶的调控作用，阐明MH可能的作用机制。

抗结核药引起的肝损伤在药物性肝损伤中占据较大比例，利福平(RFP)/异烟肼(INH)是临床广泛使用的一线抗结核药，二者联用可协同增效且减少赖药性，但会明显增加肝毒性，其增加肝毒性的原因是RFP对CYP450的诱导引起INH肝毒性代谢产物的增加，导致肝细胞的氧化损伤。具有减毒增效作用肝保护剂的开发，对临床结核病治疗过程中肝毒性的防治成为必要。本课题针对RFP/INH联合用药引起肝毒性这一临床药物不良反应，在前期湖北海棠(MH)保肝作用研究基础上，以CYP450为切入点，构建RFP/INH肝损伤小鼠动物模型，确证MH和其主要成分根皮苷对RFP/INH致肝损伤小鼠的肝脏保护作用，初步探究其发挥肝脏保护作用的机制可能与调节CYP450酶、减少INH毒性代谢产物的产生、同时抵抗INH毒性代谢产物的氧化损伤有关，并采用HPLC−MS法检测INH主要代谢产物，比较毒性代谢产物含量差异，进一步验证MH可降低主要毒性代谢产物肼的含量发挥肝脏保护作用。