Gebhardt R, Alber J, Wegner H, Mecke D
Physiologisch-chemisches Institut der Universität, Tübingen, Germany.
Biochem Pharmacol. 1994 Aug 17;48(4):761-6. doi: 10.1016/0006-2952(94)90054-x.
Isolated and cultured periportal (PP) and pericentral (PC) hepatocytes were used for studying the acinar distribution of several phase I and phase II drug metabolizing reactions and their induction by phenobarbital (PB) and 3-methylcholanthrene (MC) or a combination thereof. Ethoxycoumarin-o-deethylase (EC 1.14.14.1) (ECOD) activity was found to predominate in PC hepatocytes even after induction with MC and PB. Metabolism of biphenyl to a monosulfated product also predominated in PC hepatocytes as did the conversion of harmine to harmine glucuronide and sulfate. In contrast, metabolism of lonazolac was not zonated. The metabolism of all three substrates declined during cultivation for 24 hr and was differentially induced (biphenyl and harmine) or not affected (lonazolac) by MC or PB. Metabolic heterogeneity was best maintained by the combination of MC and PB indicating that the zonal differences are due to a specific balance of phase I and phase II reactions. Glutathione-S-transferase (GST) activities against 1-chloro-2, 4-dinitrobenzene (CDNB) were higher in PC hepatocytes and remained so after induction with PB. In contrast, GST activities against 1,2-dichloro-4-nitrobenzene (DCNB) were almost twice as high in PP cells but equilibrated due to a spontaneous increase during cultivation, particularly in PC hepatocytes. In the presence of PB or both, MC and PB, induction of the activity against DCNB occurred exclusively in the PP hepatocytes. The distribution of the GST subunits Ya and Yb1 roughly corresponded to the pattern of GST activities against CDNB and DCNB, respectively. These results agree with earlier reports demonstrating that PP and PC hepatocytes show different patterns of phase I and phase II drug metabolizing enzymes which are maintained during short-term cultivation. In vitro induction of these activities does not result in equilibration but rather maintenance or even pronounciation of these zonal differences.
分离并培养门周（PP）和中央周（PC）肝细胞，用于研究几种I相和II相药物代谢反应的腺泡分布及其被苯巴比妥（PB）和3 - 甲基胆蒽（MC）或二者组合诱导的情况。即便在用MC和PB诱导后，乙氧香豆素 - O - 脱乙基酶（EC 1.14.14.1）（ECOD）活性仍在PC肝细胞中占主导。联苯代谢为单硫酸化产物以及去氢骆驼蓬碱转化为去氢骆驼蓬碱葡糖醛酸和硫酸盐也在PC肝细胞中占主导。相比之下，氯那唑酸的代谢无区域化差异。在培养24小时期间，所有三种底物的代谢均下降，并且MC或PB对其有不同的诱导作用（联苯和去氢骆驼蓬碱）或无影响（氯那唑酸）。MC和PB的组合能最好地维持代谢异质性，这表明区域差异是由于I相和II相反应的特定平衡所致。PC肝细胞中针对1 - 氯 - 2,4 - 二硝基苯（CDNB）的谷胱甘肽 - S - 转移酶（GST）活性较高，在用PB诱导后仍保持如此。相比之下，PP细胞中针对1,2 - 二氯 - 4 - 硝基苯（DCNB）的GST活性几乎是PC肝细胞中的两倍，但由于培养过程中特别是PC肝细胞中的自发增加而达到平衡。在存在PB或同时存在MC和PB的情况下，针对DCNB的活性诱导仅发生在PP肝细胞中。GST亚基Ya和Yb1的分布大致分别对应于针对CDNB和DCNB的GST活性模式。这些结果与早期报告一致，表明PP和PC肝细胞显示出不同的I相和II相药物代谢酶模式，这些模式在短期培养期间得以维持。这些活性的体外诱导不会导致平衡，而是维持甚至增强这些区域差异。
