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Gene expression of cytochromes P 450 in liver transplants over time

  • Pharmacokinetics and Disposition
  • Published:
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Abstract

Objective

The aim of this study was to (a) quantify the gene expression of some cytochromes P 450 (CYP), especially CYP3A4, in serial biopsies from liver grafts the first year after orthoptic liver transplantation (OLT) and (b) study the relationship between hepatic CYP3A4 gene expression and plasma levels of cyclosporine and tacrolimus.

Methods

Liver tissue was obtained from surplus material of routine liver biopsies performed in 20 patients during the first year after OLT. Real-time reverse-transcription polymerase chain reaction was used for quantitative analyses of mRNA specific for CYP3A4, CYP3A5, CYP2E1 and CYP1A2 cytochromes as well as P-glycoprotein (P-gp). The gene expression of β-actin was used as an internal standard for comparisons between samples.

Results

The median value of the mRNA for all cytochromes, but not for P-gp, was found to increase significantly over time. The gene expression of CYP3A5, CYP2E1 and CYP1A2 was higher than that of CYP3A4. The gene expression of CYP3A4 was related to the plasma concentration of cyclosporine and tacrolimus, i.e. low mRNA concentrations corresponded to high serum concentration levels and vice versa. The serum concentration of bilirubin or the prothrombin index did not correlate with the gene expression level of the cytochromes.

Conclusion

The hepatic mRNA expression of CYP3A4 and the other investigated cytochromes increased during the first year after OLT. This was not the case with P-gp. Low CYP3A4 gene expression was related to high plasma levels of cyclosporine and tacrolimus and vice versa.

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Acknowledgements

We thank Mrs. Charlotte Thyr for important laboratory work with mRNA that paved the way for setting up the present methodology. We also thank Niklas Finnström, Ph.D., and Dr. Roberto Canaparo for preparing some of the standards and probes, Dr. Lisbeth Barkholt for help with collecting liver samples, all surgeons and personnel at the transplantation unit HSAS for collecting the samples during operations and research nurses Ingrid Skarp-Öberg, Maria Sveneus-Lundgren, Thomas Johansson and Aina Östman for helping in the collection of patient data. We also thank John Öhrvik, Ph.D., for excellent statistical guidance and Associate Professor Cristina Rodriguez-Antona for comparative analyses. This work was supported by the Swedish Science Council (04496), Swedish Cancer Society, the Mary Eriksson foundation, the foundation for undergraduate researchers at Uppsala University and grants from the research foundation, county of Västmanland. This study complies with the current law in Sweden.

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Authors and Affiliations

  1. Centre of Clinical Research, Central Hospital, 721 89 , Västerås, Sweden

    Mari Thörn

  2. Department of Medical Laboratory Sciences and Technology, Division of Clinical Pharmacology, Karolinska Institutet, Huddinge University Hospital, 141 86 , Stockholm, Sweden

    Stefan Lundgren & Anders Rane

  3. Department of Surgical Sciences, Division of Transplantation Surgery, Karolinska Institutet, Huddinge University Hospital, 141 86 , Stockholm, Sweden

    Gustaf Herlenius & Bo-Göran Ericzon

  4. Department of Transplantation and Liver Surgery, Sahlgrenska University Hospital, 413 45 , Gothenburg, Sweden

    Gustaf Herlenius

  5. Department of Medical Sciences, Division of Gastroenterology and Hepatology, University Hospital, 751 85 , Uppsala, Sweden

    Mari Thörn & Lars Lööf

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  1. Mari Thörn
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Correspondence to Mari Thörn.

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Thörn, M., Lundgren, S., Herlenius, G. et al. Gene expression of cytochromes P 450 in liver transplants over time. Eur J Clin Pharmacol 60, 413–420 (2004). https://doi.org/10.1007/s00228-004-0786-4

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  • DOI: https://doi.org/10.1007/s00228-004-0786-4

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