人细胞色素P450抑制剂对大鼠P450同工型的选择性：大鼠cDNA表达系统的研究

Selectivities of human cytochrome P450 inhibitors toward rat P450 isoforms: study with cDNA-expressed systems of the rat.

作者信息

Kobayashi Kaoru, Urashima Kikuko, Shimada Noriaki, Chiba Kan

机构信息

Laboratory of Pharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Chiba University, Yayoi-cho 1-33, Inage-ku, Chiba 263-8522, Japan.

出版信息

Drug Metab Dispos. 2003 Jul;31(7):833-6. doi: 10.1124/dmd.31.7.833.

DOI:10.1124/dmd.31.7.833

PMID:12814958

Abstract

The aim of this study was to determine the selectivities of chemical inhibitors for human cytochrome P450 (P450) isoforms toward the corresponding rat P450 isoforms by using cDNA-expressed rat P450s (CYP1A2, CYP2A1, CYP2C6, CYP2C11, CYP2D2, CYP2E1, CYP3A1, and CYP3A2). Among the inhibitor probes for human P450s used in this study, only sulfaphenazole showed a selective inhibitory effect on the activity of the corresponding rat P450 isoform (CYP2C6). Furafylline also preferentially inhibited the activity of rat CYP1A2. However, methoxalen and ketoconazole more strongly inhibited the activities of other P450 isoforms than those of the corresponding rat P450 isoforms, CYP2A1 and CYP3A1/2, respectively. On the other hand, quinidine and aniline had little effect on the activities of the corresponding rat P450 isoforms, CYP2D2, and rat CYP2E1, respectively. These results suggest that chemical probes that have been used for human P450 isoforms do not always exhibit the same selectivity for the corresponding rat P450 isoforms. However, it appears that sulfaphenazole can be used as a selective inhibitor for rat CYP2C6. In addition, furafylline may also be a relatively selective inhibitor for rat CYP1A2.

摘要

本研究的目的是通过使用cDNA表达的大鼠细胞色素P450（P450）同工酶（CYP1A2、CYP2A1、CYP2C6、CYP2C11、CYP2D2、CYP2E1、CYP3A1和CYP3A2）来确定化学抑制剂对人细胞色素P450（P450）同工酶相对于相应大鼠P450同工酶的选择性。在本研究中使用的人P450抑制剂探针中，只有磺胺苯吡唑对相应的大鼠P450同工酶（CYP2C6）的活性表现出选择性抑制作用。呋拉茶碱也优先抑制大鼠CYP1A2的活性。然而，甲氧沙林和酮康唑分别比相应的大鼠P450同工酶CYP2A1和CYP3A1/2更强烈地抑制其他P450同工酶的活性。另一方面，奎尼丁和苯胺分别对相应的大鼠P450同工酶CYP2D2和大鼠CYP2E1的活性几乎没有影响。这些结果表明，用于人P450同工酶的化学探针并不总是对相应的大鼠P450同工酶表现出相同的选择性。然而，磺胺苯吡唑似乎可以用作大鼠CYP2C6的选择性抑制剂。此外，呋拉茶碱也可能是大鼠CYP1A2的相对选择性抑制剂。