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Although some drugs cause drug-induced liver injury (DILI) through direct damage to hepatocytes or intereference with bile secretion, others cause delayed, often idiosyncratic, DILI with clinical features, such as mild lymphocytic infiltrate, that are reminiscent of allergic reactions involving activation of the adaptive immune system. Even in cases of direct drug-induced hepatotoxicity, infiltration of inflammatory cells into the liver is often observed, suggesting a role for the innate immune system (e.g., neutrophils, macrophages, and so on). Therefore, a variety of hypotheses for the pathogenesis of DILI center around a pathogenic role of drug- (or drug-metabolite-) specific adaptive immune cells, as well as hepatic-injury-induced innate immune responses in the development, progression, and/or resolution of DILI. [ABSTRACT FROM AUTHOR]

ABCC2/Abcc2 (MRP2/Mrp2) is expressed at major physiological barriers, such as the canalicular membrane of liver cells, kidney proximal tubule epithelial cells, enterocytes of the small and large intestine, and syncytiotrophoblast of the placenta. ABCC2/Abcc2 always localizes in the apical membranes. Although ABCC2/Abcc2 transports a variety of amphiphilic anions that belong to different classes of molecules, such as endogenous compounds (e.g., bilirubin-glucuronides), drugs, toxic chemicals, nutraceuticals, and their conjugates, it displays a preference for phase II conjugates. Phenotypically, the most obvious consequence of mutations in ABCC2 that lead to Dubin-Johnson syndrome is conjugate hyperbilirubinemia. ABCC2/Abcc2 harbors multiple binding sites and displays complex transport kinetics. [ABSTRACT FROM AUTHOR]

Hepatocytes express various transporters in the sinusoidal and canalicular membrane, which mediate hepatic uptake and canalicular efflux, forming directional transport from the sinusoid to the bile. Drug-drug interactions and genetic polymorphisms of the transporters are known to cause variations in transporter function. This review focuses on pharmacokinetic modeling of hepatobiliary transport of drugs to explain the alteration of the disposition of drugs caused by such variations, based on the clearance concept. For modeling and simulation, pravastatin and dibromosulfophthalein have been used as model compounds which are known to undergo transpoter-mediated hepatic uptake followed by biliary excretion. Pharmacokinetic modeling of hepatobiliary transport illustrates the concept of the rate-determining process in overall hepatobiliary transport. [ABSTRACT FROM AUTHOR]

Small hepatocytes (SHs) are “committed progenitor cells” that can further differentiate into mature hepatocytes (MHs). SHs can proliferate to form colonies, and the maturation of SHs occurs with the alteration of the cell shape from small and flat to large and rising/piled-up. The hepatic organoids consisting of rising/piled-up cells possess highly differentiated functions like those of MHs and anastomosing networks of bile canaliculi (BC) are developed. The cells can make bile, secrete it into BC, and the bile can be carried without leaking. Thus, the organoids consist of polarized hepatocytes and possess biochemical and physiological functions as hepatic tissue. [ABSTRACT FROM AUTHOR]

The article presents abstracts of medical research. They include "Development of Chemical Safety Toxicogenomics by "Percellome" System for the Mechanism-Based Toxicology," "A Toxicogenomics Approach to Liver Toxicants Using Human Hepatocytes," and "Toxico/Pharmacogenomics Applications that Facilitate the Understanding of Intestinal Drug Effects."

Isolated hepatocytes and liver slices, in short-term suspension or longer-term culture, offer the prospect of providing qualitative metabolic information and quantitative pharmacokinetic parameters from key animal species and man at early stages of the drug discovery–development continuum. The propensity for changes in the fidelity of drug metabolism after removal of hepatocytes from the organ has long been recognized. The many and varied approaches which have been undertaken in an attempt to compensate for physiological shortcomings of in vitro hepatocyte systems are reviewed. In this respect, short-term suspension culture may provide a baseline against which to measure the success of extended culture methods, but it should be remembered that even freshly isolated hepatocyte preparations have deficiencies and liabilities that may affect the nature of information gathered. This article discusses the current advances and shortcomings of hepatocyte suspensions and cultures, along with liver slice technology, at both quantitative and qualitative levels. [ABSTRACT FROM AUTHOR]

The use of isolated hepatocytes as an approach to evaluate hepatotoxic and hepatocarcinogenic compounds and investigate mechanisms by which chemicals induce liver lesions is well established. This review discusses techniques developed in the author's laboratory describing (1) isolation and primary culture of rodent hepatocytes detailing methods which are optimal for obtaining large numbers of viable cells, (2) DNA damage induced by physical and chemical agents in rodent hepatocytes measured as unscheduled DNA synthesis, and (3) metabolic activation of model hepatocarcinogens, their binding to DNA, and identification of individual adducts thought to be responsible for induction of DNA repair. [ABSTRACT FROM AUTHOR]

The use of primary hepatocytes is now well established for both studies of drug metabolism and enzyme induction. Cryopreservation of primary hepatocytes decreases the need for fresh liver tissue. This is especially important for research with human hepatocytes because availability of human liver tissue is limited. In this review, we summarize our research on optimization and validation of cryopreservation techniques. The critical elements for successful cryopreservation of hepalocytes are (1) the freezing protocol, (2) the concentration of the cryoprotectant [10% dimethylsulfoxide (DMSO)], (3) slow addition and removal of DMSO, (4) carbogen equilibration during isolation of hepatocytes and before cryopreservation, and (5) removal of unvital hepatocytes by Percoll centrifugation after thawing. Hepatocytes of human, monkey, dog, rat, and mouse isolated and cryopreserved by our standard procedure have a viability ≥ 80%. Metabolic capacity of cryopreserved hepatocytes determined by testosterone hydroxylation, 7-ethoxyresorufin-O-de-ethylase (EROD), 7-ethoxycoumarin-O-deethylase (ECOD), glutathione S-transferase, UDP-glucuronosyl transferase, sulfotransferase, and epoxide hydrolase activities is ≥60% of freshly isolated cells. Cryopreserved hepatocytes in suspension were successfully applied in short-term metabolism studies and as a metabolizing system in mutagenicity investigations. For instance, the complex pattern of benzo[a]pyrene metabolites including phase II metabolites formed by freshly isolated and cryopreserved hepatocytes was almost identical. For the study of enzyme induction, a longer time period and therefore cryopreserved hepatocyte cultures are required. We present a technique with cryopreserved hepatocytes that allows the induction of testosterone metabolism with similar induction factors as for fresh cultures. However, enzyme activities of induced hepatocytes and solvent controls were smaller in the cryopreserved cells. In conclusion,... [ABSTRACT FROM AUTHOR]