The applicability of rat and human liver slices to the study of mechanisms of hepatic drug uptake

Olinga, Peter; Hof, Ingrid H.; Merema, Marjolijn T.; Smit, Maaike; Jager, Marina H. de; Swart, Piet J; Slooff, Maarten J. H.; Meijer, Dirk K. F.; Groothuis, Geny M. M.

doi:10.1016/s1056-8719(01)00127-7

Cited by 62 publications

(31 citation statements)

References 24 publications

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“…In contrast to the results (for humans) reported here, which show digoxin is not a substrate of hepatic OATPs, it has been shown that digoxin is a substrate of hepatic Oatp1a4 in rats (Noé et al, 1997), although there is no ortholog of Oatp1a4 in humans. In addition, amiodarone, quinidine, and rifampicin have been shown to inhibit uptake of digoxin in rat hepatocytes (Lambert et al, 1989;Hedman and Meijer, 1998;Olinga et al, 2001;Kodawara et al, 2002;Lam and Benet, 2004;Lau et al, 2004). None of these compounds inhibited digoxin uptake in SCHH in the current study.…”

Section: Discussionmentioning

confidence: 41%

Characterization of Digoxin Uptake in Sandwich-Cultured Human Hepatocytes

Kimoto¹,

Chupka²,

Xiao³

et al. 2010

Drug Metab Dispos

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ABSTRACT:Digoxin is a drug that is commonly used to treat congestive heart failure. Because of digoxin's narrow therapeutic index, patients are susceptible to drug-drug interaction-mediated cardiotoxicity. Digoxin is primarily cleared renally; however, a significant component of clearance is due to multidrug resistance 1-mediated transport into bile. Digoxin is reported to be actively transported into human hepatocytes by the organic anion-transporting polypeptide 1B3 (OATP1B3); however, further characterization has not been fully described.

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Section: Discussionmentioning

confidence: 41%

Characterization of Digoxin Uptake in Sandwich-Cultured Human Hepatocytes

Kimoto¹,

Chupka²,

Xiao³

et al. 2010

Drug Metab Dispos

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“…This finding was ascertained by both morphological and biochemical analysis of triglycerides. In this regard, triglyceride levels progressively increased during incubation in the presence of ethanol, reaching an almost In summary, PCLS have recently been used by other investigators studying the toxicological effects of a number of drugs and toxins [10,13,32,34]. It was the purpose of this study to determine whether PCLS could be used as a model system to study the effects of ethanol on the liver.…”

Section: Discussionmentioning

confidence: 98%

“…PCLS have been used previously for a variety of metabolic and toxicological studies [10][11][12][13], and appear to be applicable for ethanol hepatotoxicity studies. In this model, normal lobular hepatic architecture is maintained, and the cell-cell and cellmatrix interactions mimic the in vivo situation.…”

Section: Introductionmentioning

confidence: 99%

An in vitro method of alcoholic liver injury using precision-cut liver slices from rats

Klassen

Thiele

Duryee

et al. 2008

Biochemical Pharmacology

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Alcohol abuse results in liver injury, but investigations into the mechanism(s) for this injury have been hampered by the lack of appropriate in vitro culture models in which to conduct in depth and specific studies. In order to overcome these shortcomings, we have developed the use of precision-cut liver slices (PCLS) as an in vitro culture model in which to investigate how ethanol causes alcohol-induced liver injury. In these studies, it was shown that the PCLS retained excellent viability as determined by lactate dehydrogenase and adenosine triphosphate (ATP) levels over a 96-h period of incubation. More importantly, the major enzymes of ethanol detoxification; alcohol dehydrogenase, aldehyde dehydrogenase, and cytochrome P4502E1, remained active and PCLS readily metabolized ethanol and produced acetaldehyde. Within 24 h and continuing up to 96 h the PCLS developed fatty livers and demonstrated an increase in the redox state. These PCLS secreted albumin, and albumin secretion was decreased by ethanol treatment. All of these impairments were reversed following the addition of 4-methylpyrazole, which is an inhibitor of ethanol metabolism. Therefore, this model system appears to mimic the ethanol-induced changes in the liver that have been previously reported in human and animal studies, and may be a useful model for the study of alcoholic liver disease.

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“…For the reverse transcription polymerase chain reaction (RT-PCR) analyses, an additional 12 patients with HCV infection (3 women, 9 men; mean age 39 Ϯ 3.3 years, range 21-53 years; ISHAK A-D 4.8 Ϯ 0.6, F 2.2 Ϯ 0.6) were included. Explants from freshly isolated liver of healthy and steatotic individuals as well as liver biopsies of HCV-infected patients were precisely divided into 125 mm 3 cubes under sterile conditions 25,26 and incubated with 1 mL of medium in 24-well plates under gentle shaking. PHHs were isolated from healthy liver as described 27 and provided by Cytonet (Hannover, Germany).…”

Section: Methodsmentioning

confidence: 99%

Increased hepatotoxicity of tumor necrosis factor–related apoptosis-inducing ligand in diseased human liver

Fischer²,

et al. 2007

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Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis in tumor cells but not in most normal cells and has therefore been proposed as a promising antitumor agent. Recent experiments suggested that isolated primary human hepatocytes but not monkey liver cells are susceptible to certain TRAIL agonists, raising concerns about the use of TRAIL in cancer treatment. Whether TRAIL indeed exerts hepatotoxicity in vivo and how this is influenced by chemotherapeutic drugs or liver disease are completely unknown. Employing different forms of recombinant TRAIL, we found that the cytokine can induce proapoptotic caspase activity in isolated human hepatocytes. However in marked contrast, these different TRAIL preparations induced little or no cytotoxicity when incubated with tissue explants of fresh healthy liver, an experimental model that may more faithfully mimic the in vivo situation. In healthy liver, TRAIL induced apoptosis only when combined with histone deacetylase inhibitors. Strikingly, however, TRAIL alone triggered massive apoptosis accompanied by caspase activation in tissue explants from patients with liver steatosis or hepatitis C viral infection. This enhanced sensitivity of diseased liver was associated with an increased expression of TRAIL receptors and up-regulation of proapoptotic Bcl-2 proteins. Conclusion: These results suggest that clinical trials should be performed with great caution when TRAIL is combined with chemotherapy or administered to patients with inflammatory liver diseases.

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The applicability of rat and human liver slices to the study of mechanisms of hepatic drug uptake

Cited by 62 publications

References 24 publications

Characterization of Digoxin Uptake in Sandwich-Cultured Human Hepatocytes

Characterization of Digoxin Uptake in Sandwich-Cultured Human Hepatocytes

An in vitro method of alcoholic liver injury using precision-cut liver slices from rats

Increased hepatotoxicity of tumor necrosis factor–related apoptosis-inducing ligand in diseased human liver

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