Bars R G, Mitchell A M, Wolf C R, Elcombe C R
Biochemical Toxicology Section, I.C.I. Central Toxicology Laboratory, Macclesfield, Cheshire, U.K.
Biochem J. 1989 Aug 15;262(1):151-8. doi: 10.1042/bj2620151.
Primary cultures of rat hepatocytes were exposed to phenobarbitone, clofibric acid, beta-naphthoflavone, isosafrole or dexamethasone for 3 days, and the induction of several cytochrome P-450 isoenzymes was demonstrated by increased catalytic activity, by Western blotting and by immunocytochemistry. The profiles of isoenzymes induced in vitro were compared with those induced in liver microsomes of rats dosed with the same agents. Clofibric acid, an agent which has not been thoroughly investigated previously, was shown to induce both in vivo and in vitro several P-450 isoenzymes normally inducible by phenobarbitone (PB1a, PB3a and PB3b) or steroids (PB2c). Immunocytochemical studies demonstrated that the inducible isoenzymes of cytochrome P-450 are not distributed evenly throughout the hepatocyte population, and increasing concentrations of phenobarbitone or beta-naphthoflavone in the medium results in an increasing proportion of 'induced' cells. However, whereas maximal concentrations of beta-naphthoflavone resulted in virtually all cells containing induced levels of MC1b, a maximal concentration of phenobarbitone resulted in only 30% of the cells containing induced levels of PB3a/PB3b. These results are discussed in relation to the heterogeneous distribution and induction of cytochrome P-450 in the intact liver.
将大鼠肝细胞原代培养物暴露于苯巴比妥、氯贝酸、β-萘黄酮、异黄樟素或地塞米松中3天，通过催化活性增加、蛋白质免疫印迹法和免疫细胞化学法证实了几种细胞色素P - 450同工酶的诱导。将体外诱导的同工酶谱与用相同药物给药的大鼠肝微粒体中诱导的同工酶谱进行比较。氯贝酸是一种先前未被彻底研究的药物，结果表明它在体内和体外均可诱导几种通常由苯巴比妥（PB1a、PB3a和PB3b）或类固醇（PB2c）诱导的P - 450同工酶。免疫细胞化学研究表明，细胞色素P - 450的可诱导同工酶在整个肝细胞群体中分布不均，培养基中苯巴比妥或β-萘黄酮浓度的增加导致“诱导”细胞的比例增加。然而，虽然β-萘黄酮的最大浓度导致几乎所有细胞都含有诱导水平的MC1b，但苯巴比妥的最大浓度仅导致30%的细胞含有诱导水平的PB3a/PB3b。结合完整肝脏中细胞色素P - 450的异质性分布和诱导情况对这些结果进行了讨论。
