Gene expression of cytochromes P450 in liver transplants over time.
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 beta-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.


CONCLUSIONS
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.
Thörn
Mari
M
Centre of Clinical Research, Central Hospital, 721 89 Västerås, Sweden. Mari.Thorn@telia.com
Lundgren
Stefan
S
Herlenius
Gustaf
G
Ericzon
Bo-Göran
BG
Lööf
Lars
L
Rane
Anders
A
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis / Q000235:genetics; D000328:Adult; D001663:Bilirubin / Q000097:blood; D016572:Cyclosporine / Q000097:blood; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis* / Q000235:genetics*; D018076:DNA, Complementary / Q000096:biosynthesis / Q000302:isolation & purification; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D006801:Humans; D007166:Immunosuppressive Agents / Q000097:blood; D007527:Isoenzymes / Q000096:biosynthesis / Q000235:genetics; D008099:Liver / Q000201:enzymology*; D016031:Liver Transplantation / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D011516:Prothrombin / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis / Q000302:isolation & purification; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016559:Tacrolimus / Q000097:blood; D013997:Time Factors
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018076:DNA, Complementary; D007166:Immunosuppressive Agents; D007527:Isoenzymes; D012333:RNA, Messenger; D016572:Cyclosporine; D011516:Prothrombin; D003577:Cytochrome P-450 Enzyme System; D001663:Bilirubin; D016559:Tacrolimus