Preliminary report on the effect of xenoperfusion with human blood on cyclosporin A metabolism and cytochrome-P-4503A4-mRNA expression in a pig liver perfusion model.
OBJECTIVE
Little is known about the effect of ischemia/reperfusion with xenogenic blood on function and gene expression of CYP3A4, the enzyme largely responsible for the metabolism of the immunosuppressants Cyclosporin A (CsA) and Tacrolimus.


METHODS
In a pig liver perfusion model, we have compared the effect of perfusion (3 h) after 20 h cold storage, with either pig or human blood on CsA metabolism and CYP3A4-mRNA expression. mCYP3A4-mRNA was quantified by RT-PCR, CsA and its major metabolites AM1, AM9, AM4N by RP-HPLC. IL-6 served as inflammation marker, GLDH and ALT to estimate tissue damage.


RESULTS
Inflammatory response and tissue damage were more extensive during xenoperfusion. CYP3A4 expression decreased similarly during xenogenic and allogenic perfusion. CsA conversion to its metabolites was also comparable during xeno- and alloperfusion.


CONCLUSIONS
There is no evidence that during the early reperfusion period pig liver CYP3A4 is severely affected if the organ is xenoperfused with human blood in comparison with alloperfusion.
Wieland
E
E
Abteilung Klinische Chemie, Georg-August-Universität Göttingen, Robert-Koch-Street 40, D-37075, Göttingen, Germany. ewieland@med.uni-goettingen.de
Shipkova
M
M
Schütz
E
E
Braun
F
F
Niedmann
P
P
Armstrong
V W
VW
Ringe
B
B
Svinarov
D A
DA
Oellerich
M
M
D000818:Animals; D001219:Aspartate Aminotransferases / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D016572:Cyclosporine / Q000494:pharmacology*; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D005969:Glutamate Dehydrogenase / Q000378:metabolism; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D015850:Interleukin-6 / Q000378:metabolism; D007511:Ischemia; D008099:Liver / Q000378:metabolism*; D006899:Mixed Function Oxygenases / Q000096:biosynthesis*; D010477:Perfusion / Q000379:methods*; D012333:RNA, Messenger / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013552:Swine; D013997:Time Factors
D007166:Immunosuppressive Agents; D015850:Interleukin-6; D012333:RNA, Messenger; D016572:Cyclosporine; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D005969:Glutamate Dehydrogenase; D001219:Aspartate Aminotransferases