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Gene expression of cytochromes P450 in liver transplants over time
Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
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2004 In: European Journal of Clinical Pharmacology, ISSN 0031-6970, Vol. 60, no 6, 413-420 p.Article in journal (Refereed) Published
Place, publisher, year, edition, pages
2004. Vol. 60, no 6, 413-420 p.
Identifiers
URN: urn:nbn:se:uu:diva-93029OAI: oai:DiVA.org:uu-93029DiVA: diva2:166381
Available from: 2005-05-09 Created: 2005-05-09Bibliographically approved
In thesis
1. Qualitative and Quantitative Assessment of Cytochromes P450 mRNA in Human: Studies in the Liver, Blood and Gastrointestinal Mucosa
Open this publication in new window or tab >>Qualitative and Quantitative Assessment of Cytochromes P450 mRNA in Human: Studies in the Liver, Blood and Gastrointestinal Mucosa
2005 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Drugs and other foreign compounds must often be metabolised before they can be excreted from the body. One enzyme system that is responsible for this is the cytochrome P450 gene family (CYP). In this thesis, new sensitive molecular techniques have been used to study the human gene expression of some CYP enzymes, as well as the P-glycoprotein transporter (P-gp). The aim was to evaluate whether tissues other than the liver, e.g. the blood, could be used to assess an individual's drug metabolic capacity. Another aim was to investigate the gene expression in relation to the liver transplant process and a third aim was to evaluate the expression in gastrointestinal mucosa in both normal and inflamed mucosa.

We evaluated the CYP gene expression in paired specimens of liver and blood but found no correlation in the expression patterns of these two tissues. Instead, we found the opposite pattern, where, for example, CYP1B1 had the highest expression in the blood but the lowest in the liver and CYP2E1 was the enzyme with the highest expression in the liver. In an investigation of the expression of four different CYP enzymes and P-gp in liver transplants before and during the first year after transplantation, we found that the levels of all the CYP enzymes but not P-gp increased with time. We also found that the expression of CYP3A4 was inversely related to the normalised plasma levels of the immunosuppressive drugs cyclosporine and tacrolimus.

In the gastrointestinal tract, CYP2E1 was the enzyme with the highest mRNA expression compared with CYP3A4, CYP3A5 and the transporter P-gp. CYP3A4 has its highest expression in the duodenum compared with the expression in the stomach and the colon. CYP3A5 is expressed at a higher level than CYP3A4 in the colon. P-gp expression levels increase through the gastrointestinal tract to the left colon. Gene expression levels of CYP2E1 and CYP3A4 decrease in severely inflamed rectal mucosa.

In conclusion, this is a sensitive method for studying gene activity in a clinical situation, even though at this point we are not able to use blood or gastrointestinal mucosa as “surrogate” tissue to estimate an individual’s drug metabolic capacity. The studies in liver transplants and gastrointestinal mucosa are unique in that the gene expression is investigated during a clinical course of events.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2005. 57 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 37
Keyword
Medical sciences, cytochrome P450, CYP1A2, CYP1B1, CYP2E1, CYP3A4, CYP3A5, P-gp, gene expression, RT-PCR, liver, blood, gastrointestinal mucosa, MEDICIN OCH VÅRD
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-5786 (URN)91-554-6245-6 (ISBN)
Public defence
2005-05-30, Samlingssalen, Ing. 29 Centrallasarettet, Västerås, 13:15
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Supervisors
Available from: 2005-05-09 Created: 2005-05-09Bibliographically approved

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