Induction of CYP3A isoforms in cultured precisioncut human liver slices

Lake, Brian G.; Ball, S.; Renwick, A.B.; Tredger, J. Michael; Kao, J.; Beamand, J.A.; Price, Roger J.

doi:10.1080/004982597239921

Cited by 36 publications

(14 citation statements)

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“…The concentrations of BNF, DEX, LANS, NaPB, and RIF were selected from previous in vitro studies in either human hepatocytes (Curi-Pedrosa et al, 1994;Donato et al, 1995;Meunier et al, 2000;Sahi et al, 2000) or liver slices (Lake et al, , 1997. For MCP, a rodent peroxisome proliferator and CYP4A inducer, the concentration selected was based on that used in previous studies with cultured rat and human liver slices (Beamand et al, 1993;Lake et al, 1996).…”

Section: P450 Induction In Human Liver Slicesmentioning

confidence: 99%

“…For example, Aroclor 1254, ␤-naphthoflavone (BNF), 3,3Ј-diindolylmethane, omeprazole, and 2,3,7,8-tetrachlorodibenzo-p-dioxin have been reported to induce CYP1A enzymes in cultured human liver slices (Lake et al, , 1998Olson et al, 1997;Drahushuk et al, 1998;Glöckner et al, 1999). In one study rifampicin (RIF) was reported to induce CYP3A4 (Lake et al, 1997), and in a recently published abstract, cyclophosphamide and phenobarbital were reported to induce CYP2B6 and CYP3A4 in cultured human liver slices (Martin et al, 2002).…”

mentioning

confidence: 99%

“…Unlike previous studies (Lake et al, , 1997(Lake et al, , 1998Drahushuk et al, 1998;Glöckner et al, 1999), where relatively small numbers (up to six preparations) of human liver slices were evaluated, in the present study liver slice preparations from 11 donors were examined. The model inducers selected comprised BNF, dexamethasone (DEX), lansoprazole (LANS), RIF, and sodium phenobarbital (NaPB), which are all known to induce various P450 enzymes in human hepatocytes (Curi-Pedrosa et al, 1994;Donato et al, 1995;Maurel, 1996;Chang et al, 1997;Pelkonen et al, 1998;Meunier et al, 2000;Gerbal-Chaloin et al, 2001).…”

mentioning

confidence: 99%

“…Precision-cut liver slices were treated with the test compounds for 72 h, as this treatment period has been previously shown to be suitable to observe induction of P450 enzyme activities and apoprotein levels in cultured human liver slices (Lake et al, , 1997(Lake et al, , 1998. Levels of CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2D6, CYP2E1, CYP3A4, CYP3A5, and CYP4A11 apoproteins were quantified by immunoblotting with a panel of fully characterized monospecific antipeptide antibodies (Edwards et al, 1998).…”

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confidence: 99%

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Induction of Cytochrome P450 Enzymes in Cultured Precision-Cut Human Liver Slices

Edwards¹,

Price²,

Watts³

et al. 2003

Drug Metab Dispos

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This article is available online at http://dmd.aspetjournals.org ABSTRACT:Precision-cut human liver slices obtained from 11 donors were cultured for 72 h in a defined medium (serum free Williams' medium E) supplemented with 0.1 M insulin and 0.1 M dexamethasone (DEX). Liver slices were treated with 50 M concentrations of ␤ -naphthoflavone (BNF), lansoprazole, rifampicin (RIF), DEX and methylclofenapate and 500 M sodium phenobarbital (NaPB). The relative apoprotein levels of 12 cytochrome P450 (P450) enzymes were determined in liver slice microsomes using a panel of antipeptide antibodies. Treatment with BNF significantly induced mean levels of CYP1A2 apoprotein to 160% of levels in 72-h control (no test compound) human liver slice microsomes. NaPB significantly induced levels of CYP3A4 apoprotein to 255% of control and RIF significantly induced levels of CYP2C19 and CYP3A4 apoproteins to 265 and 330% of control, respectively. In addition, treatment with RIF increased levels of CYP2A6 apoprotein to 205% of control, and treatment with both NaPB and RIF increased levels of CYP2B6 apoprotein to 370 and 615% of control, respectively. However, these increases were not statistically significant, owing to a variable response between liver slice preparations from different subjects, this being apparent for all inducible P450s. In contrast, none of the compounds examined significantly increased levels of CYP2C8, CYP2C9, CYP2D6, CYP2E1, and CYP4A11 apoproteins. Levels of CYP1A1 apoprotein were not detected in any liver slice sample, either before or after treatment with the model inducers. Overall, these results demonstrate the utility of cultured human liver slices for assessing the effects of chemicals on P450 enzymes.

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Section: P450 Induction In Human Liver Slicesmentioning

confidence: 99%

mentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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Induction of Cytochrome P450 Enzymes in Cultured Precision-Cut Human Liver Slices

Edwards¹,

Price²,

Watts³

et al. 2003

Drug Metab Dispos

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“…In the past decade, precision-cut liver slices have been successfully used as an in vitro model for biotransformation (Dogterom and Rothuizen, 1993;Ball et al, 1996;Hashemi et al, 1999), hepatotoxicity (Wormser et al, 1990;Miller et al, 1993), and enzyme induction studies (Lake et al, 1997) in a variety of animal species. Important determinants in this successful application of liver slices are undoubtedly the maintenance of normal tissue architecture, cell heterogeneity, and cell-cell communications within the livers' original tissue matrix.…”

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confidence: 99%

Utility of Rat Liver Slices to Estimate Hepatic Clearance for Application in Physiologically Based Pharmacokinetic Modeling: A Study with Tolbutamide, a Compound with Low Extraction Efficiency

Haenen

Rompelberg²,

Twillert³

et al. 2002

Drug Metab Dispos

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ABSTRACT:Liver slice experiments were performed to determine the slice intrinsic clearance and to extrapolate this to the in vivo liver intrinsic clearance in a physiologically based pharmacokinetic (PBPK)-like approach. Precision-cut liver slices were incubated with different initial concentrations of tolbutamide, and the time series of parent and metabolite concentrations were measured in slice and incubation medium. A mathematical model was built that modeled the uptake of tolbutamide and its metabolism in the liver slice. In addition, binding of tolbutamide to cellular constituents and partition over the water and lipid phase were accounted for by the model. Model analysis imposed sampling of parent compound in slice and of metabolites pooled from slice and medium. The model was calibrated to the data, fitting the intrinsic clearance, the parent In the past decade, precision-cut liver slices have been successfully used as an in vitro model for biotransformation (Dogterom and Rothuizen, 1993;Ball et al., 1996;Hashemi et al., 1999), hepatotoxicity (Wormser et al., 1990;Miller et al., 1993), and enzyme induction studies (Lake et al., 1997) in a variety of animal species. Important determinants in this successful application of liver slices are undoubtedly the maintenance of normal tissue architecture, cell heterogeneity, and cell-cell communications within the livers' original tissue matrix.However, a drawback of liver slices often addressed in studies predicting rates of metabolism is their diffusional limitations (Ekins et al., 1995;Worboys et al., 1997). The outer cell layers of liver slices are directly exposed to incubation media; however, the inner cell layers are only exposed to the test compound when it has traveled through or around the outer cell layers. This phenomenon has been visualized using a fluorescent dye (Ekins et al., 1995). Diffusional limitations have often led to underevaluation of in vivo intrinsic clearance rates when liver slice data are normalized for hepatocellularity (Worboys et al., 1996a,b).These problems, however, can be counteracted when appropriate modeling of in vitro data is incorporated in the prediction strategy. In this respect, it is important to note that Worboys et al. (1997) assessed drug metabolism in rat liver slices by analyzing experimental data with a classical one-compartment model. However, the liver slice model consists of two physically different phases (i.e., slice and surrounding incubation medium), and hence, a two-compartment model seems more appropriate. In contrast to other liver slice models designed to predict rates of metabolism we developed a model that consists of a physicochemical part, a mathematical part, and an observable part. Our liver slice model takes into consideration processes of transport, partitioning, and elimination of drug and/or its metabolites, which leads to the identification of the ultimate parameter: the slice metabolic rate constant CL s . 1 The development of our rat liver slice model can be seen as a first step to improve t...

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Precision‐Cut Tissue Slices: A SuitableIn VitroSystem for the Study of the Induction of Drug‐Metabolizing Enzyme Systems

Ioannides

Lake

2012

Encyclopedia of Drug Metabolism and Interactions

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Most xenobiotic‐metabolising enzyme systems, and in particular the cytochromes P450, may be markedly up‐regulated following exposure to inducing agents. A rise in activity of these enzyme systems may lead to drug interactions with adverse or even fatal outcomes. Furthermore, modulation of these enzyme systems may bring about a profound change in an individual's susceptibility to a chemical toxin. The use of precision‐cut tissue slices as an in vitro system allows the rapid and facile investigation of the potential of a chemical to induce cytochrome P450 and other xenobiotic‐metabolising enzymes in different animal species, as well as in humans. Various tissues (e.g. liver, lung, intestine) can be used, and the effect of chemicals investigated in a concentration‐dependent manner, and employing a number of endpoints.

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Induction of CYP3A isoforms in cultured precisioncut human liver slices

Cited by 36 publications

References 14 publications

Induction of Cytochrome P450 Enzymes in Cultured Precision-Cut Human Liver Slices

Induction of Cytochrome P450 Enzymes in Cultured Precision-Cut Human Liver Slices

Utility of Rat Liver Slices to Estimate Hepatic Clearance for Application in Physiologically Based Pharmacokinetic Modeling: A Study with Tolbutamide, a Compound with Low Extraction Efficiency

Precision‐Cut Tissue Slices: A SuitableIn VitroSystem for the Study of the Induction of Drug‐Metabolizing Enzyme Systems

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