Nakajima M, Kobayashi K, Shimada N, Tokudome S, Yamamoto T, Kuroiwa Y
Department of Clinical Pharmacy, School of Pharmaceutical Sciences, Showa University, Tokyo, Japan.
Br J Clin Pharmacol. 1998 Jul;46(1):55-62. doi: 10.1046/j.1365-2125.1998.00048.x.
Mexiletine has been reported to be hydroxylated by cytochrome P450 2D6 (CYP2D6) in humans. However, the involvement of CYP1A2 in the metabolism of mexiletine has been proposed based on the interaction with theophylline which is mainly metabolized by CYP1A2. The aim of this study was to clarify the role of human CYP1A2 in mexiletine metabolism.
Human CYP isoforms involved in mexiletine metabolism were investigated using microsomes from human liver and B-lymphoblastoid cells expressing human CYPs. The contributions of CYP1A2 and CYP2D6 to mexiletine metabolism were estimated by the relative activity factor (RAF).
Mexiletine p- and 2-hydroxylase activities in human liver microsomes were inhibited by ethoxyresorufin and furafylline as well as quinidine. Mexiletine p- and 2-hydroxylase activities in microsomes from nine human livers correlated significantly with bufuralol 1'-hydroxylase activity (r = 0.907, P < 0.001 and r = 0.886, P < 0.01, respectively). Microsomes of B-lymphoblastoid cells expressing human CYP1A2 exhibited lower mexiletine p- and 2-hydroxylase activities than those expressing human CYP2D6. It was estimated by RAF that the major isoform involved in mexiletine metabolism was CYP2D6, and the contribution of CYPIA2 to both mexiletine p- and 2-hydroxylase activities was 7-30% in human liver microsomes. However, the Km values of the expressed CYP1A2 (approximately 15 microM) were almost identical with those of the expressed CYP2D6 (approximately 22 microM) and human liver microsomes.
Mexiletine is a substrate of CYP1A2. The data obtained in this study suggest that the interaction of mexiletine with theophylline might be due to competitive inhibition of CYP1A2.
据报道，美西律在人体内可被细胞色素P450 2D6（CYP2D6）羟基化。然而，基于美西律与主要由CYP1A2代谢的茶碱之间的相互作用，有人提出CYP1A2参与了美西律的代谢。本研究的目的是阐明人CYP1A2在美西律代谢中的作用。
使用来自人肝脏的微粒体和表达人细胞色素P450同工酶的B淋巴细胞系来研究参与美西律代谢的人细胞色素P450同工酶。通过相对活性因子（RAF）评估CYP1A2和CYP2D6对美西律代谢的贡献。
人肝脏微粒体中美西律的对羟基化酶和2-羟基化酶活性受到乙氧芴香豆素、呋拉茶碱以及奎尼丁的抑制。来自9个人肝脏的微粒体中美西律的对羟基化酶和2-羟基化酶活性与布非洛尔1'-羟基化酶活性显著相关（分别为r = 0.907，P < 0.001和r = 0.886，P < 0.01）。表达人CYP1A2的B淋巴细胞系微粒体表现出比表达人CYP2D6的微粒体更低的美西律对羟基化酶和2-羟基化酶活性。通过RAF估计，参与美西律代谢的主要同工酶是CYP2D6，在人肝脏微粒体中，CYPIA2对美西律对羟基化酶和2-羟基化酶活性的贡献为7%-30%。然而，表达的CYP1A2的Km值（约15 microM）与表达的CYP2D6（约22 microM）和人肝脏微粒体的Km值几乎相同。
美西律是CYP1A2的底物。本研究获得的数据表明，美西律与茶碱之间的相互作用可能是由于对CYP1A2的竞争性抑制。
