Bioorganic Chemistry ( IF 4.5 ) Pub Date : 2021-11-15 , DOI: 10.1016/j.bioorg.2021.105478 Kai Wang 1 , Tingting Zhang 2 , Jinqiu Rao 2 , Ting Peng 2 , Qing Gao 3 , Xinchi Feng 1 , Feng Qiu 2
Linderane (LDR) is a main furan-containing sesquiterpenoid of the common herbal medicine Lindera aggregata (Sims) Kosterm. Our early study indicated that LDR led to mechanism-based inactivation (MBI) of CYP2C9 in vitro, implying possible drug-drug interactions (DDIs) in clinic. In the present study, influence of LDR on the pharmacokinetics of the corresponding hydroxylated metabolites of CYP2C9 substrates in rats was investigated. Pharmacokinetic studies revealed that pretreatment with LDR at 20 mg/kg for 15 days inhibited the metabolism of both tolbutamide and warfarin catalyzed by CYP2C9. As for 4-hydroxytolbutamide, the Cmax was decreased, the t1/2z was prolonged, and the Vz/F was increased, all with significant difference. As for 7-hydroxywarfarin, the AUC0-t/AUC0-∞ and CLz/F were significantly decreased and increased, respectively. Furthermore, the underlying molecular mechanisms based on MBI of CYP2C9 by LDR were revealed. Two reactive metabolites of LDR, furanoepoxide and γ-ketoenal intermediates were identified in CYP2C9 recombinant enzyme incubation systems. Correspondingly, covalent modifications of lysine and cysteine residues of CYP2C9 protein were discovered in the CYP2C9 incubation system treated with LDR. The formation of protein adducts exhibited obvious time- and dose-dependence, which is consistent with the trend of enzyme inhibition caused by LDR in vitro. In addition to the apoprotein of CYP2C9, the heme content was significantly reduced after co-incubation with LDR. These data revealed that modification of both apoprotein and heme of CYP2C9 by reactive metabolites of LDR led to MBI of CYP2C9, therefore resulting in the inhibition of biotransformation of CYP2C9 substrates to their corresponding metabolites in vivo.
中文翻译:
基于机制的 CYP2C9 失活和分子机制的林德烷诱导的药物-药物相互作用
Linderane (LDR) 是常见草药Lindera aggregata (Sims) Kosterm 的主要含呋喃倍半萜类化合物。我们的早期研究表明,LDR 导致 CYP2C9在体外的基于机制的失活 (MBI) ,这意味着临床上可能存在药物-药物相互作用 (DDI)。在本研究中,研究了 LDR 对大鼠 CYP2C9 底物相应羟基化代谢物药代动力学的影响。药代动力学研究表明,用 20 mg/kg LDR 预处理 15 天可抑制 CYP2C9 催化的甲苯磺丁脲和华法林的代谢。对于 4-羟基甲苯磺丁脲,C max降低,t 1/2z 延长,Vz/F 增加,均具有显着性差异。7-羟基华法林的AUC 0-t /AUC 0-∞和CLz/F分别显着降低和升高。此外,揭示了基于 LDR 对 CYP2C9 的 MBI 的潜在分子机制。在 CYP2C9 重组酶培养系统中鉴定了 LDR 的两种反应性代谢物,呋喃环氧化物和γ-酮醛中间体。相应地,在用LDR处理的CYP2C9孵育系统中发现了CYP2C9蛋白赖氨酸和半胱氨酸残基的共价修饰。蛋白加合物的形成具有明显的时间和剂量依赖性,这与体外LDR引起的酶抑制趋势一致。. 除了 CYP2C9 的载脂蛋白外,与 LDR 共孵育后血红素含量显着降低。这些数据表明,LDR 的反应性代谢物对 CYP2C9 的载脂蛋白和血红素的修饰导致 CYP2C9 的 MBI,因此导致 CYP2C9 底物在体内向其相应代谢物的生物转化的抑制。