Ketoconazole impairs biliary excretory function in the isolated perfused rat liver

Summary The effects of ketoconazole (KT) on the hepatic excretory function was investigated in the isolated perfused rat liver. KT, at the concentrations of 5 × 10^–5 M or 10^–4 M caused dose-dependent decreases of the biliary bile acid concentration and excretion rate, with no significant effect on bile flow rates. Neither dose altered perfusate flow through the liver. Furthermore, at the same two concentrations, KT impaired the sulfobromophthalein transport in a dose-dependent manner. In contrast, the drug did not alter ¹⁴C-sucrose bile to perfusate ratio and did not cause enzyme release from the liver into the perfusate. The study demonstrates that KT possesses an intrinsic toxicity in the isolated perfused rat liver and suggests caution in the use of this drug in hepatopathic patients. Send offprint requests to G. B. Gaeta at the above address     

Influence of viability on bromosulfophthalein uptake by isolated hepatocytes

Summary The initial rates of BSP uptake by isolated hepatocytes were compared in cells of good and poor viability. Cells with impaired viability were obtained by ageing or by accident also in fresh preparations. Viability was judged by trypan blue stainability, membrane potential and respiratory parameters indicative for energy state, substrate supply and plasma membrane permeability changes. It was found that concomitant with impaired viability there was a decline of uptake rates at low and an increase at high BSP concentrations with a crossover point at 10 M as manifest in an increase of K _m and V. Simultaneously, the affinity and size of the membrane bound fraction decreases. The results give kinetic support to the supposition that it is the decreased uptake from plasma to liver that is responsible for the prolonged plasma retention times in the liver function test of patients with impaired hepatobiliary function.Abbreviations BSP Bromosulfophthalein - CCP Carbonylcyanide m-chlorophenylhydrazone A preliminary report was given on the Spring Meeting of the German Pharmacological Society at Mainz, March 23–26, 1976 [Schwenk, M., Burr, R., Pfaff, E.: Naunyn-Schmiedeberg's Arch. Pharmacol. 293, R48 (1976)].This study was supported by the Deutsche Forschungsgemeinschaft. The authors wish to thank Mrs. Sylvia Kasperek for skilful technical assistance.     

New results on saturation phenomena in BSP metabolism: the role of free and conjugated BSP

The fact that the role of conjugation cannot be neglected in the definition and evaluation of the different maximal transfer rates introduced in the literature (T_m, L_m) is demonstrated. Free and conjugated BSP were measured both in blood and bile during constant infusion of free BSP in man. These data proved very useful to develop a careful model of BSP metabolism able to interpret all major known facts in saturation conditions. The model shows that, in the conditions used for the Wheelter-test, biliary excretion is saturated both for free and conjugated BSP. At higher infusion rates, there is also saturation of the hepatic uptake of conjugated BSP. No other processes are saturated in these conditions. Lastly, free and conjugated BSP are excreted at a maximal rate that is not dependent on their respective amounts in the liver; this suggests the existence of independent transport mechanism in biliary excretion for free and conjugated BSP during the infusion of free BSP.     

BSP siRNA 的构建及其对成骨样细胞株MC3T3-E1相关基因表达的影响

目的 构建BSP干扰表达载体,有效沉默小鼠成骨样细胞MC3T3-E1 Subclone 14细胞的BSP基因表达,研究其对MC3T3-E1 Subclone 14增殖分化过程中OCN等成骨相关基因表达的影响.方法 ①利用互联网资源针对BSP基因mRNA序列设计四条可能的小干扰RNA(siRNA),将这四条小干扰RNA插...     

SPARC and DNA methylation: Possible diagnostic and therapeutic implications in gastrointestinal cancers

DNA methylation is a major contributor to epigenetic alterations and as such is a potential biomarker and therapeutic target in gastrointestinal malignancies. DNA methylation is commonly observed in several Gastrointestinal (GI) malignancies including pancreatic and colorectal cancer. Methylation results in decreased expression of tumor suppressor genes. Secreted protein acidic and rich in cysteine (SPARC) is a tumor suppressor gene that can be functionally inactivated through methylation. SPARC is commonly dysregulated in GI malignancies. Inhibition of DNA methylation can reverse the silencing of SPARC. In the present review, we will discuss recent advances in our understanding of the features of DNA methylation that pertain to SPARC, focusing on their functional and clinical relevance in GI carcinogenesis.     

釉基质蛋白对大鼠骨髓基质细胞合成非胶原蛋白的影响

目的探讨釉基质蛋白对大鼠骨髓基质细胞合成非胶原蛋白的影响。方法采用全骨髓法培养大鼠骨髓基质细胞,通过免疫细胞化学和图像分析方法观察釉基质蛋白对骨髓基质细胞合成骨桥蛋白、骨涎蛋白的影响。结果实验组非胶原蛋白合成明显强于对照组。结论一定浓度的釉基质蛋白可以有效促进骨桥蛋白、骨涎蛋白的合成。