Raunio H, Kojo A, Juvonen R, Honkakoski P, Järvinen P, Lang M A, Vähäkangas K, Gelboin H V, Park S S, Pelkonen O
Department of Pharmacology, University of Oulu, Finland.
Biochem Pharmacol. 1988 Nov 1;37(21):4141-7. doi: 10.1016/0006-2952(88)90108-6.
The effects of 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP) and pyrazole on mouse hepatic cytochrome P-450 isozyme expression were compared to the P-450 induction pattern elicited by phenobarbital. TCPOBOP and PB administration caused a similar induction profile by increasing microsomal protein and cytochrome P-450 content and the catalytic activities of several monooxygenases in DBA/2N and AKR/J mice. There were, however, several quantitative and some qualitative differences in the induction profile caused by phenobarbital and TCPOBOP. A few strain-related differences were also observed. Immunoblot analysis with polyclonal anti-coumarin hydroxylase (P-450Coh) antibody and epitope-specific monoclonal antibodies 1-7-1 and 2-66-3 showed that both phenobarbital and TCPOBOP increase the amount of P450IIB and P-450Coh. TCPOBOP caused a more pronounced increase in the amount of P-450IIB than phenobarbital, and TCPOBOP also caused an increase in the amount of P-450IA2. These data suggest that in the mouse, TCPOBOP increases mainly the expression of P-450 isozymes responsive to phenobarbital. The effects of pyrazole differed greatly from those caused by TCPOBOP and phenobarbital. In the DBA/2N mice, pyrazole increased coumarin 7-hydroxylation 9.4-fold, whereas in the AKR/J mice the activity was induced only to a level equivalent to the DBA/2N basal level. In immunoblot experiments with anti-P-450Coh antibody, the amount of P-450Coh was considerably higher in DBA/2N mice treated with phenobarbital, TCPOBOP, or pyrazole in comparison with the AKR/J mice, indicating a strain specificity in the inducibility of coumarin 7-hydroxylase by pyrazole.
将1,4 - 双[2 - (3,5 - 二氯吡啶氧基)]苯（TCPOBOP）和吡唑对小鼠肝脏细胞色素P - 450同工酶表达的影响与苯巴比妥引发的P - 450诱导模式进行了比较。给予TCPOBOP和苯巴比妥后，通过增加微粒体蛋白和细胞色素P - 450含量以及几种单加氧酶在DBA/2N和AKR/J小鼠中的催化活性，引起了相似的诱导模式。然而，苯巴比妥和TCPOBOP引起的诱导模式在数量和一些质量上存在差异。还观察到了一些品系相关的差异。用多克隆抗香豆素羟化酶（P - 450Coh）抗体以及表位特异性单克隆抗体1 - 7 - 1和2 - 66 - 3进行的免疫印迹分析表明，苯巴比妥和TCPOBOP均增加了P450IIB和P - 450Coh的量。TCPOBOP使P - 450IIB的量增加比苯巴比妥更明显，并且TCPOBOP还使P - 450IA2的量增加。这些数据表明，在小鼠中，TCPOBOP主要增加对苯巴比妥有反应的P - 450同工酶的表达。吡唑的作用与TCPOBOP和苯巴比妥引起的作用有很大不同。在DBA/2N小鼠中，吡唑使香豆素7 - 羟化增加9.4倍，而在AKR/J小鼠中，该活性仅诱导至相当于DBA/2N基础水平。在用抗P - 450Coh抗体进行的免疫印迹实验中，与AKR/J小鼠相比，用苯巴比妥、TCPOBOP或吡唑处理的DBA/2N小鼠中P - 450Coh的量明显更高，表明吡唑对香豆素7 - 羟化酶诱导的品系特异性。
