This set of experiments is the first of a series designed to explore facets of cell proliferation of hepatocytes during the carcinogenic process induced in liver by chemical carcinogens. A rat model for hepatocarcinogenesis, the resistant hepatocyte model, was used. A major advantage of this model is the unusual degree of synchrony in the early steps. Carcinogenesis was initiated by the adminis...

PURPOSE Primary mammalian hepatocytes largely retain their liver-specific functions when they are freshly derived from donors. However, long-term cultures of functional hepatocytes are difficult to establish. To increase the longevity and maintain the differentiated functions of hepatocytes in primary culture, cells can be cultured in a sandwich configuration of collagen. In such a configuratio...

The intrinsic metabolic clearance of saquinavir, nelfinavir, and ritonavir was determined over a range of concentrations (0.02-20 microM) in both rat liver microsomes and fresh isolated rat hepatocytes in suspension. Clearance values were found to be concentration dependent for both systems, and at low concentrations, microsomal clearance was much greater (7-14-fold) than in hepatocytes. Kineti...

α1-Antitrypsin deficiency is an inherited condition that causes liver disease and emphysema. The normal function of this protein, which is synthesized by the liver, is to inhibit neutrophil elastase, a protease that degrades connective tissue of the lung. In the classical form of the disease, inefficient secretion of a mutant α1-antitrypsin protein (AAT-Z) results in its accumulation within hep...

Cholesterol 7 alpha-hydroxylase, the rate-limiting enzyme in bile salt synthesis from cholesterol is a P450 enzyme (CYP7A). Its expression and activity are regulated by bile salts, cholesterol, hormones and a circadian modulator. Here we define the hepatocytes contributing to the expression of the rat CYP7A gene during its in vivo circadian variation. The diurnal expression of the CYP7A messeng...

The effects of warm machine perfusion preservation of liver grafts donated after cardiac death on the intracellular three-dimensional ultrastructure of the organelles in hepatocytes remain unclear. Here we analyzed comparatively the ultrastructure of the endomembrane systems in porcine hepatocytes under warm ischemia and successive hypothermic and midthermic machine perfusion preservation, a ty...

Human upcyte® hepatocytes are proliferating hepatocytes that retain many characteristics of primary human hepatocytes. We conducted a comprehensive evaluation of the application of second-generation upcyte® hepatocytes from four donors for inhibition and induction assays using a selection of reference inhibitors and inducers. CYP1A2, CYP2B6, CYP2C9, and CYP3A4 were reproducibly inhibited in a c...

The liver plays a major role in the regulation of glucose homoeostasis. Evidence from liver-specific insulin receptor knockout mice (LIRKO) suggested that insulin's direct and indirect effects on glucose utilization by the liver both require the presence of hepatic insulin receptors (IR). To address this issue, we have generated immortalized neonatal hepatocytes bearing (HIR LoxP) or not (HIR K...

Cytochrome P450 (P450) induction may have considerable implications for drug therapy. Therefore, understanding the induction potential of a new chemical entity at an early stage in discovery is crucial to reduce the risk of failure in the clinic and help the identification of noninducing chemical structures. Availability of human viable tissue often limits evaluation of induction potential in h...