Yoshida T, Kobayashi Y, Masuko T, Hashimoto Y, Kuroiwa Y
Department of Biochemical Toxicology, School of Pharmaceutical Sciences, Showa University, Tokyo, Japan.
Toxicol Lett. 1995 Mar;76(2):145-53. doi: 10.1016/0378-4274(94)03208-o.
We compared the effects of 3 dipyridyl isomers, 2,2'-dipyridyl, 2,4'-dipyridyl and 4,4'-dipyridyl, on hepatic microsomal heme oxygenase and drug-metabolizing enzyme activities in male rats. 2,2'-Dipyridyl increased cytochrome P450 (P450) content at lower doses, but decreased with increasing dose levels. Immunoblot analysis revealed that 2,2'-dipyridyl did not induce both P450 1A1/2 and P450 2B1/2, in contrast to 2,4'- and 4,4'-dipyridyls, both of which were inducers of either P450 1A1/2 and/or P450 2B1/2. Some drug-metabolizing enzyme activities gradually declined with the increasing dose level of 2,2'-dipyridyl. 2,2'-Dipyridyl was able to induce hepatic microsomal heme oxygenase in a dose-dependent manner, but 2,4'- and 4,4'-dipyridyls did not, even at the highest dose (0.80 mmol/kg) examined. Treatment of rats with 2,2'-dipyridyl resulted in the increase of glutathione (GSH) content in a dose-dependent manner, but not 4-substituted isomers. A time course study with 2,2'-dipyridyl revealed that it produced a significant decrease in hepatic GSH content at early time periods (2-6 h) after its administration with an inverse increase in heme oxygenase activity. The present investigation has revealed that in contrast to the induction of P450 by 4-substituted dipyridyl compounds, 2,2'-dipyridyl is a novel inducer of hepatic microsomal heme oxygenase, together with the change in hepatic GSH content. This study would provide information on the differential effects of simple dipyridyl isomers on hepatic enzymes involved in heme and drug metabolism.
我们比较了三种联吡啶异构体，即2,2'-联吡啶、2,4'-联吡啶和4,4'-联吡啶，对雄性大鼠肝微粒体血红素加氧酶和药物代谢酶活性的影响。低剂量时，2,2'-联吡啶可增加细胞色素P450（P450）含量，但随着剂量水平的增加而降低。免疫印迹分析显示，与2,4'-联吡啶和4,4'-联吡啶不同，2,2'-联吡啶不会诱导P450 1A1/2和P450 2B1/2，而后两者均为P450 1A1/2和/或P450 2B1/2的诱导剂。随着2,2'-联吡啶剂量水平的增加，一些药物代谢酶活性逐渐下降。2,2'-联吡啶能够以剂量依赖的方式诱导肝微粒体血红素加氧酶，但2,4'-联吡啶和4,4'-联吡啶即使在最高剂量（0.80 mmol/kg）下也不能诱导。用2,2'-联吡啶处理大鼠会导致谷胱甘肽（GSH）含量以剂量依赖的方式增加，但4-取代异构体则不会。对2,2'-联吡啶进行的时间进程研究表明，给药后早期（2 - 6小时）肝脏GSH含量显著降低，同时血红素加氧酶活性呈反向增加。本研究表明，与4-取代联吡啶化合物诱导P450不同，2,2'-联吡啶是肝微粒体血红素加氧酶的新型诱导剂，同时还会引起肝脏GSH含量的变化。这项研究将提供有关简单联吡啶异构体对参与血红素和药物代谢的肝酶的不同作用的信息。
