Induction of Cytochrome P450 (CYP)1A1, CYP1A2, and CYP3A4 but Not of CYP2C9, CYP2C19, Multidrug Resistance (MDR-1) and Multidrug Resistance Associated Protein (MRP-1) by Prototypical Inducers in Human Hepatocytes

Köhler, Christoph; Kostrubsky, Vsevolod E.; Jäger, Dana; Lehmann, Thomas; Runge, Dieter; May, Ursula; Stolz, Donna B.; Strom, Stephen C.; Fleig, Wolfgang E.; Michalopoulos, George K.

doi:10.1006/bbrc.2000.2902

Cited by 106 publications

(67 citation statements)

References 32 publications

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“…Yet in human primary hepatocytes, PB treatment had no effect on MDR1 (Runge et al, 2000). Results presented here also show no significant changes in rat mdr1a or mdr1b mRNA levels upon in vivo treatment with PB.…”

Section: Brady Et Alcontrasting

confidence: 43%

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Tissue Distribution and Chemical Induction of Multiple Drug Resistance Genes in Rats

Cherrington²,

et al. 2002

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ABSTRACT:Multiple drug resistance (mdr) genes encode P-glycoprotein, which is responsible for resistance to some cancer chemotherapeutic drugs and efflux of xenobiotics of cells. Thus, mdr can protect organs from xenobiotics. In rats, there are two mdr1 genes capable of xenobiotic transport, mdr1a and mdr1b. The purpose of this study was to determine the tissue distribution of rat mdr1a and mdr1b mRNA and whether microsomal enzyme inducers that increase phase I and II drug-metabolizing enzymes coordinately regulate mdr1a and/or mdr1b. The mRNA levels of mdr1a and mdr1b were determined using branched-DNA signal amplification technology. The highest level of expression of mdr1a mRNA was observed in the gastrointestinal tract, with levels increasing, respectively, from duodenum, jejunum, and ileum to large intestine. Expression levels of mdr1a mRNA in the cerebral cortex, cerebellum, kidney, lung, and liver were less than one-tenth of that in the ileum. The tissue distribution of mdr1b mRNA was similar to mdr1a with highest expression in the gastrointestinal tract but only about 3-fold higher than in most other tissues. The induction of mdr1a and mdr1b mRNA transcripts in liver, kidney, and ileum by treatment of rats with 18 chemicals representing aryl hydrocarbon receptor ligands, constitutive androstane receptor ligands, pregnane X receptor ligands, peroxisome proliferator-activated receptor ligands, electrophile-response-element activators, and CYP4502E1 inducers was assessed. Hepatic, renal, and intestinal expression of mdr1a and mdr1b mRNA were not significantly altered by treatment of rats with any of these classes of ligands. In conclusion, the primary expression of rat mdr1 genes is in the gastrointestinal tract where they are thought to function to decrease the absorption of some xenobiotics. Rat mdr1 gene expression is not readily increased by microsomal enzyme inducers in rats through coordinate mechanisms with phase I and II drugmetabolizing enzymes.

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Section: Brady Et Alcontrasting

confidence: 43%

“…However, in primary human hepatocytes from two donors, Runge et al (2000) did not see an increase in MDR1 protein with rifampin treatment. Whereas the report of Synold et al (2001) indicates that rifampicin causes a moderate induction of hepatic MDR1 gene expression in primary human hepatocytes.…”

Section: Brady Et Almentioning

confidence: 70%

Tissue Distribution and Chemical Induction of Multiple Drug Resistance Genes in Rats

Cherrington²,

et al. 2002

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“…Human AE cells also expressed genes involved in drug metabolism, such as CYP 2C9, CYP 2D6, and CYP 3A4. It is necessary to investigate whether hAE cells possess drug metabolizing activity (e.g., testosterone-6β-hydroxylase activity of CYP3A4-expressing cells (Runge et al, 2000)). …”

Section: Discussionmentioning

confidence: 99%

Human Amniotic Epithelial Cells Possess Hepatocyte-like Characteristics and Functions

Takashima

Ise

Zhao

et al. 2004

Cell Struct. Funct.

134

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ABSTRACT. Hepatocyte transplantation is expected to become a novel method for treatment of liver disease. However, many questions remain regarding this approach, especially concerning donor cells. To evaluate whether human amniotic epithelial cells can be used as a cell source for hepatocyte transplantation, hepatic gene expression and functions of human amniotic epithelial cells were analyzed. Reverse transcription-polymerase chain reaction analysis demonstrated that human amniotic epithelial cells expressed albumin, α1-antitrypsin, and other hepatocyte-related genes. Cultivated human amniotic epithelial cells demonstrated albumin production, glycogen storage, and albumin secretion consistent with the hepatocyte gene expression profile. In organ culture, the amnion secreted 30-fold larger amounts of albumin than human amniotic epithelial cells in monolayer culture. Moreover, in organ culture the amnion also secreted α1-antitrypsin. Following transplantation into mice, the amnion survived and secreted albumin. These observations suggest that transplantation of human amniotic epithelial cells and/or amnion could be novel therapeutic strategy for treatment of hepatic diseases, including α1-antitrypsin deficiency.

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“…A major disadvantage is the lack of available material, which is mainly donated by patients with liver resections due to cancer. to counter this deficiency the long-term and serum-free cultivation of human hepatocytes was improved, mainly by adaptation of the culture medium (Runge et al, 1999;Runge et al, 2000;Ferrini et al, 1997). the generated HHMM (Human Hepatocyte Maintenance Medium) maintains human hepatocytes in a dif-of CYP450 proteins and other liver specific functions depend more on cell-cell than on cell-matrix contacts (Hamilton et al, 2001;Isom et al, 1984).…”

Section: Introductionmentioning

confidence: 99%

Long term cultures of primary human hepatocytes as an alternative to drug testing in animals

Ullrich¹,

Stolz²,

Ellis³

et al. 2009

ALTEX

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Induction of Cytochrome P450 (CYP)1A1, CYP1A2, and CYP3A4 but Not of CYP2C9, CYP2C19, Multidrug Resistance (MDR-1) and Multidrug Resistance Associated Protein (MRP-1) by Prototypical Inducers in Human Hepatocytes

Cited by 106 publications

References 32 publications

Tissue Distribution and Chemical Induction of Multiple Drug Resistance Genes in Rats

Tissue Distribution and Chemical Induction of Multiple Drug Resistance Genes in Rats

Human Amniotic Epithelial Cells Possess Hepatocyte-like Characteristics and Functions

Long term cultures of primary human hepatocytes as an alternative to drug testing in animals

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