Characteristics of β-oxidative and reductive metabolism on the acyl side chain of cinnamic acid and its analogues in rats
Characteristics of β-oxidative and reductive metabolism on the acyl side chain of cinnamic acid and its analogues in rats
复制标题
肉桂酸及其类似物酰基侧链在大鼠体内β-氧化还原代谢特征
DOI：
10.1038/s41401-019-0218-8
复制
发表时间：
2019
影响因子：
8.2
通讯作者：
Xiao-dong Liu
中科院分区：
文献类型：
--
作者：
Kai-jing Zhao;Yang Chen;Shi-jin Hong;Yi-ting Yang;Jiong Xu;Han-yu Yang;Liang Zhu;Ming Liu;Qiu-shi Xie;Xian-ge Tang;Ting-ting Yang;Ya-qian Zhou;Li Liu;Xiao-dong Liu
肉桂酸及其类似物（阿罗格雷和奥扎格雷）经历链缩短在本研究中，我们利用原代大鼠肝细胞、肝线粒体、和微粒体系统。开发了包括母体化合物和代谢物的房室模型来表征体内β-大鼠静脉注射母体化合物后的氧化和还原代谢。拟合的体内总清除率值进一步与充分搅拌模型预测的体外值进行比较。我们发现肝微粒体CYP 450不催化三种化合物的β-氧化或还原代谢。类似于脂肪酸的β-氧化，β-氧化代谢主要发生在线粒体，对ATP、CoA和NAD~+高度依赖，脂肪酸和NADH抑制β-氧化代谢;还原代谢发生在线粒体和微粒体，线粒体的还原是ATP、CoA和NAD（P）H依赖的，是可逆的，而烯酰还原酶抑制剂三氯生可抑制这种作用。在微粒体中，和NADPH依赖性，但受三氯生的影响很小。使用房室模型成功拟合了氧化代谢物和还原代谢物。估计的总体内清除率值与肝细胞和细胞器的预测值一致，这些结果表明肝线粒体和微粒体在肉桂酸及其类似物沿着的酰基侧链的β-氧化和还原代谢中的作用及其代谢特征。
Cinnamic acid and its analogues (pyragrel and ozagrel) undergo chain-shortened (β-oxidative) and reductive metabolism on acyl side chain.In this study,we characterized the β-oxidative and reductive metabolism on acyl side chain of cinnamic acid and its analogues using primary rat hepatocytes,hepatic mitochondrial,and microsomal systems.A compartmental model including parent compounds and metabolites was developed to characterize in vivo β-oxidative and reductive metabolism following an intravenous dose of parent compounds to rats.The fitted total in vivo clearance values were further compared with the in vitro values predicted by the well-stirred model.We showed that hepatic microsomal CYP450s did not catalyze β-oxidative or reductive metabolism of the three compounds.Similar to β-oxidation of fatty acids,β-oxidative metabolism on their acyl side chain occurred mainly in mitochondria,which was highly dependent on ATP,CoA and NAD~+.Fatty acids and NADH inhibited the β-oxidative metabolism.Reductive metabolism occurred in both mitochondria and microsomes.Reduction in mitochondria was ATP-,CoA-,and NAD(P)H-dependent and reversible,which was suppressed by enoyl reductase inhibitor triclosan.Reduction in microsomes was ATP-,CoA-,and NADPH-dependent but little affected by triclosan.Both plasma concentrations of β-oxidative metabolites and reductive metabolites were successfully fitted using the compartmental model.The estimated total in vivo clearance values were consistent with those predicted from hepatocytes and organelles,implicating significance of in vitro kinetics.These findings demonstrate the roles of hepatic mitochondria and microsomes in β-oxidative and reductive metabolism on acyl side chain of cinnamic acid and its analogues along with their metabolic characteristics.