Groothuis G M, Meijer D K
Department of Pharmacology and Therapeutics, University Center for Pharmacy, Groningen, The Netherlands.
Enzyme. 1992;46(1-3):94-138. doi: 10.1159/000468780.
In the past two decades many studies have been devoted to the involvement of the periportal (zone-1) and perivenous (zone-3) hepatocytes in bile formation and hepatobiliary transport of endogenous and exogenous compounds. It became clear that such a heterogeneity in transport function can, in principle, be due to the different localization of the cells in the acinus with respect to the incoming blood, to intrinsic differences between the cells or to both. In this review we first discuss the techniques used to study hepatocyte heterogeneity in hepatobiliary transport function. Combinations of such techniques can be used to discriminate between cellular heterogeneity due to acinar localization as opposed to intrinsic differences. These techniques include: normal and retrograde perfusions of isolated perfused livers; autoradiographic, fluorimetric and histochemical localization of injected substrates; separation of isolated hepatocytes into fractions enriched in periportal and perivenous cells; measurements of fluorescent surface signals with microlight guides; selective zonal toxicity, and pharmacokinetic modelling and analysis. Subsequently, for each of the rate-limiting steps in the hepatobiliary transport of organic compounds, the basic mechanisms are summarized and the available knowledge on the involvement of the cells from the various zones in these transport steps is discussed. The available literature data indicate that heterogeneity in transport function is often due to the localization of the cells in the acinus: the periportal cells are the first to come into contact with the portal blood and are thus exposed to the highest substrate concentration. Consequently they obtain the most prominent task in further disposition of the particular compound. It follows that the extent of involvement of the perivenous cells in drug disposition is implicitly determined by the activity of the periportal cells. Because of the potential saturation of elimination processes in the periportal cells, the involvement of perivenous cells may vary with the input concentration. In addition, real intrinsic differences have been established in the hepatobiliary transport of some substrates. These are probably based on differences in the cellular content of carrier- and receptor-binding and/or metabolizing proteins. In some cases these intrinsic differences may be secondary to existing sinusoidal gradients of endogenous compounds, such as O2, amino acids, bile acids or monosaccharides. Yet, data on the heterogeneity of hepatocytes in the various transport steps are far from complete or are even totally lacking, especially for human liver. A multi-experimental approach and advanced technology will be needed in the future to gain more insight into the acinar organization of bile formation and hepatobiliary transport of drugs in the human.
在过去二十年中，许多研究致力于探讨汇管区（1区）和中央静脉周围（3区）肝细胞在胆汁形成以及内源性和外源性化合物的肝胆转运中的作用。很明显，这种转运功能的异质性原则上可能是由于细胞在腺泡中相对于进入血液的不同定位、细胞之间的内在差异或两者兼而有之。在这篇综述中，我们首先讨论用于研究肝细胞在肝胆转运功能方面异质性的技术。这些技术的组合可用于区分由于腺泡定位引起的细胞异质性与内在差异。这些技术包括：离体灌注肝脏的正常和逆行灌注；注射底物的放射自显影、荧光测定和组织化学定位；将分离的肝细胞分离为富含汇管区和中央静脉周围细胞的组分；用微导光管测量荧光表面信号；选择性区域毒性，以及药代动力学建模与分析。随后，针对有机化合物肝胆转运中的每个限速步骤，总结了基本机制，并讨论了关于不同区域细胞参与这些转运步骤的现有知识。现有文献数据表明，转运功能的异质性通常是由于细胞在腺泡中的定位：汇管区细胞最先接触门静脉血，因此暴露于最高的底物浓度。因此，它们在特定化合物的进一步处置中承担着最突出的任务。由此可见，中央静脉周围细胞在药物处置中的参与程度隐含地由汇管区细胞的活性决定。由于汇管区细胞消除过程的潜在饱和，中央静脉周围细胞的参与程度可能随输入浓度而变化。此外，已确定在某些底物的肝胆转运中存在真正的内在差异。这些差异可能基于载体结合、受体结合和/或代谢蛋白的细胞含量差异。在某些情况下，这些内在差异可能是内源性化合物（如氧气、氨基酸、胆汁酸或单糖）现有窦状梯度的继发结果。然而，关于肝细胞在各种转运步骤中的异质性的数据远未完整，甚至完全缺乏，尤其是关于人类肝脏的。未来需要采用多实验方法和先进技术，以更深入地了解人类胆汁形成的腺泡组织和药物的肝胆转运。
